Compendium

Protein Families & Drug Target Catalog — GPCRs, Kinases, NRs, Ion Channels, Proteases

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Protein Families & Drug Target Catalog

This Tier 3 family index aggregates the canonical druggable target classes of the human proteome together with the marketed and late-clinical drugs that hit them. It is organised around target class rather than therapy area, because most modern pharma R&D is class-mechanistic (a kinase team works across oncology, immunology, fibrosis). Numbers, prices, and approval years are as of mid-2026. SI units throughout; concentrations in mol/L (M = mol/L), distances in m, masses in g (Da for protein mass; 1 Da = 1.66054 × 10⁻²⁷ kg).

Druggable proteome — landscape

The foundational survey is Hopkins & Groom (2002, Nature Reviews Drug Discovery) which estimated ~3,000 druggable human proteins of which ~600–1,500 were “disease-relevant”. The 2017 update by Santos et al. (Nature Reviews Drug Discovery, 2017) counted 667 unique molecular drug targets behind 1,578 FDA-approved drugs (small-molecule + biologics), and projected a druggable proteome of ~3,500 proteins. As of 2026 the count of unique approved targets is ~720.

Distribution of approved-drug targets by family (Santos 2017 plus 2024 update):

ClassShare of approved drugsHuman family sizeNotes
GPCRs~35 %~800 (~400 non-olfactory)Lefkowitz–Kobilka Nobel 2012
Kinases~25 %518 (Manning 2002)Most rapidly-growing class
Ion channels~15 %~400Voltage- + ligand-gated
Nuclear receptors~10 %48 (Mangelsdorf 1995)Steroid + metabolic + orphan
Proteases~5 %~600 (degradome)Aspartic, serine, cysteine, metallo, threonine
Other enzymes~10 %ManyOxidoreductases, transferases, lyases, isomerases, ligases

The remaining ~3 % is split between transporters (SLC + ABC), epigenetic readers/writers/erasers, structural proteins, and recent additions (PROTAC E3-ligase recruiters such as cereblon CRBN and VHL).

GPCRs (G Protein-Coupled Receptors)

Seven-transmembrane-helix superfamily; signal through heterotrimeric G proteins (Gαs/Gαi/Gαq/Gα12) and arrestins. Class assignments use the GRAFS nomenclature (Glutamate, Rhodopsin, Adhesion, Frizzled, Secretin — Fredriksson 2003) but pharmacology still mostly uses the Kolakowski A–F system.

Class A (rhodopsin-like)

~700 of the ~800 human GPCRs. Most pharmacological targets.

  • Adrenergic — α1 (A/B/D; tamsulosin Flomax for BPH), α2 (A/B/C; clonidine, dexmedetomidine Precedex sedation), β1 (cardiac; metoprolol Lopressor, bisoprolol, atenolol — class III heart-failure backbone), β2 (bronchial; salbutamol Ventolin, salmeterol Serevent, formoterol, vilanterol; LABA + ICS combos Advair/Seretide GSK, Symbicort AstraZeneca, Breo Ellipta, Trelegy triple), β3 (mirabegron Myrbetriq overactive bladder; vibegron Gemtesa Sumitomo)
  • Muscarinic acetylcholine — M1–M5; tiotropium Spiriva (LAMA), umeclidinium, glycopyrrolate, aclidinium; pirenzepine M1-preferring (legacy); xanomeline (KarXT Bristol-Myers Squibb 2024 schizophrenia approval — M1/M4 agonist + trospium peripheral blocker; first new-mechanism antipsychotic in decades)
  • Opioid — μ MOR (morphine, oxycodone OxyContin Purdue, fentanyl Duragesic, methadone, buprenorphine Suboxone, tapentadol Nucynta; naloxone Narcan reversal; naltrexone Vivitrol; antagonists for opioid-induced constipation methylnaltrexone Relistor + naloxegol Movantik), δ DOR, κ KOR (nalfurafine Remitch for pruritus Japan; difelikefalin Korsuva CKD pruritus 2021; ziconotide synthetic ω-conotoxin not GPCR but related neuropathic pain); biased agonism: oliceridine Olinvyk (Trevena 2020 G-protein-biased μ — modest commercial outcome)
  • Dopamine — D1, D2 (haloperidol, risperidone, olanzapine Zyprexa, quetiapine Seroquel, aripiprazole Abilify partial agonist; D2 + 5HT2A “atypicals”), D3 (cariprazine Vraylar, brexpiprazole Rexulti), D4 (clozapine), D5; Parkinson’s agonists: pramipexole Mirapex, ropinirole Requip, rotigotine Neupro patch, apomorphine Apokyn rescue
  • Serotonin (5-HT) — 1A (buspirone Buspar), 1B/1D triptans (sumatriptan Imitrex GSK, rizatriptan Maxalt, eletriptan Relpax, lasmiditan Reyvow 5HT1F Eli Lilly 2019), 2A (atypical antipsychotics; psychedelics psilocybin Compass Pathways COMP360 Phase III TRD; MDMA-AT Lykos rejected 2024), 2B (cardiotoxic — fenfluramine pulled, but fenfluramine Fintepla returned for Dravet 2020), 2C (lorcaserin Belviq pulled 2020 cancer signal), 3 (ondansetron Zofran, granisetron, palonosetron — chemo-induced nausea), 6, 7
  • Histamine — H1 (chlorpheniramine, diphenhydramine; second-gen non-sedating loratadine Claritin, cetirizine Zyrtec, fexofenadine Allegra; bilastine), H2 (cimetidine Tagamet first blockbuster 1976, ranitidine Zantac NDMA-contaminated withdrawn 2020, famotidine Pepcid), H3 (pitolisant Wakix for narcolepsy 2016), H4
  • Cannabinoid — CB1 (rimonabant Acomplia withdrawn 2008 suicidality; nabilone Cesamet); CB2 — peripheral immune
  • Chemokine — CXCR4 (plerixafor Mozobil HSC mobilisation; mavorixafor X4 Pharma); CCR5 (maraviroc Selzentry HIV entry inhibitor); CCR9 (vercirnon failed); CXCR1/2 (navarixin); CCR4 (mogamulizumab Poteligeo CTCL)
  • Angiotensin AT1 — sartans (losartan Cozaar Merck first; valsartan Diovan Novartis, candesartan Atacand, irbesartan Avapro, olmesartan Benicar, telmisartan Micardis, azilsartan Edarbi); + ARNi sacubitril/valsartan Entresto Novartis $6B 2023
  • Endothelin ETA/ETB — bosentan Tracleer Actelion→J&J, ambrisentan Letairis, macitentan Opsumit, aprocitentan Tryvio (resistant hypertension 2024)
  • Leukotriene CysLT1 — montelukast Singulair, zafirlukast; LTB4 BLT — none approved
  • Prostaglandin/Thromboxane — TP, EP1–4, FP, DP1/2, IP; latanoprost Xalatan + travoprost + bimatoprost Lumigan (FP glaucoma); ramatroban Baynas; selexipag Uptravi IP (PAH)
  • Bradykinin B1, B2 — icatibant Firazyr HAE
  • Neuropeptide / orexin — OX1/OX2 antagonists (DORA) suvorexant Belsomra Merck, lemborexant Dayvigo Eisai, daridorexant Quviviq Idorsia (insomnia)
  • Vasopressin V1a, V1b, V2 — tolvaptan Samsca/Jynarque (SIADH + ADPKD), conivaptan
  • Oxytocin — atosiban Tractocile (preterm labour Europe)
  • GnRH — leuprolide Lupron Depot AbbVie + Eligard, goserelin Zoladex, triptorelin Trelstar, degarelix Firmagon antagonist; relugolix Orgovyx oral antagonist (Sumitomo; PC); elagolix Orilissa (endometriosis); linzagolix Yselty
  • Calcium-sensing CaSR — cinacalcet Sensipar Amgen, etelcalcetide Parsabiv (i.v. SHPT)
  • Free fatty acid FFA1/GPR40 (fasiglifam terminated; piragliatin), FFA2 + FFA3 (gut microbiome SCFA sensing)
  • Sphingosine-1-phosphate S1P1–S1P5 — fingolimod Gilenya (MS first oral 2010), siponimod Mayzent, ozanimod Zeposia, ponesimod Ponvory, etrasimod Velsipity (UC 2023)
  • Adenosine A1, A2A, A2B, A3 — regadenoson Lexiscan (stress test), adenosine itself for SVT; istradefylline Nourianz (PD adjunct); etrumadenant + ciforadenant immuno-oncology trials

Class B (secretin family)

24 receptors; large extracellular domain binds peptide ligands.

  • GLP-1 receptor — the most consequential drug class of 2020s
    • Semaglutide — Ozempic (T2DM s.c. 0.5/1/2 mg weekly), Wegovy (obesity s.c. up to 2.4 mg), Rybelsus (oral 7/14 mg with SNAC absorption enhancer). Novo Nordisk; ~US$25 billion 2024 revenue across franchise
    • Tirzepatide — Mounjaro / Zepbound. Eli Lilly. Dual GLP-1 + GIP agonist; SURPASS + SURMOUNT trials — ~22 % weight loss at 15 mg/wk in SURMOUNT-1. ~US$18 billion 2024
    • Liraglutide — Victoza/Saxenda Novo (daily; older)
    • Exenatide — Byetta + Bydureon AstraZeneca (legacy)
    • Dulaglutide — Trulicity Lilly weekly
    • Lixisenatide — Adlyxin Sanofi (discontinued US 2023)
    • Pipeline — retatrutide Lilly (GLP-1 + GIP + glucagon triple; SURPASS / TRIUMPH Phase III ~24 % weight loss), orforglipron Lilly (oral non-peptide small-molecule GLP-1RA; ACHIEVE + ATTAIN Phase III), CagriSema Novo (cagrilintide amylin + semaglutide), survodutide BI/Zealand (GLP-1/glucagon MASH), mazdutide Innovent/Lilly (China), danuglipron Pfizer discontinued April 2024 LFTs
  • GIP — receptor co-targeted by tirzepatide
  • Glucagon receptor — co-targeted by triagonists
  • PTH/PTHrP — teriparatide Forteo Lilly (PTH 1-34 osteoporosis), abaloparatide Tymlos Radius (PTHrP analog)
  • CRF1/CRF2 — corticotropin-releasing factor; crinecerfont Crenessity Neurocrine 2024 (congenital adrenal hyperplasia)
  • Calcitonin — calcitonin salmon (osteoporosis legacy)
  • Secretin / VIP / PACAP — research

Class C (metabotropic glutamate, GABAB, taste, calcium)

  • mGluR1–8 in three groups (I = mGluR1/5 Gq; II = mGluR2/3 Gi; III = mGluR4/6/7/8 Gi). Targets investigated for schizophrenia, anxiety, addiction; LY2140023 (pomaglumetad) Lilly failed. TS-161 Taisho/Sage. Mavoglurant + basimglurant Fragile X failed. dipraglurant for Parkinson’s LID
  • GABAB — baclofen Lioresal (spasticity); arbaclofen
  • CaSR — see above
  • T1R taste sweet — extra-oral roles in gut endocrine cells; T2R bitter — airway smooth muscle (denatonium)

Class F (frizzled / smoothened)

10 frizzled (FZD1–10) + smoothened (SMO). Wnt + Hedgehog signalling.

  • SMO antagonists — vismodegib Erivedge Roche (BCC), sonidegib Odomzo Sun Pharma, glasdegib Daurismo Pfizer (AML adjunct)
  • FZD targeting research — vantictumab + ipafricept terminated; OMP-18R5

GPCR drug design topics

Biased agonism / functional selectivity — ligand stabilises receptor conformations that preferentially recruit G protein versus β-arrestin. Oliceridine and TRV027 attempted to exploit this. Allosteric modulators — PAM positive (cinacalcet CaSR, maraviroc CCR5 — actually allosteric), NAM negative (mavoglurant mGluR5), SAM silent. Photopharmacology — azobenzene ligand switches research. GPCR cryo-EM — 600+ structures since 2018 (β1AR Rasmussen 2007 + β2AR Cherezov 2007 X-ray was the breakthrough); active-state with mini-Gs/Gq/Gi or nanobody Nb80; Stevens, Kobilka, Steyaert, García-Nafría labs.

Kinases

The 518-member kinome was catalogued by Manning et al. (2002, Science; “The protein kinase complement of the human genome”). Eukaryotic protein kinase (ePK) superfamily share a bilobal fold with the ATP-binding cleft between the small N-lobe (β-sheet) and large C-lobe (α-helical), activation loop, and the conserved DFG (Asp-Phe-Gly) motif at its N-terminus. The catalytic lysine (~K72 in PKA) coordinates ATP α + β phosphates; the catalytic loop HRD motif positions the substrate. Type I inhibitors bind active DFG-in; Type II bind inactive DFG-out (imatinib classic); Type III allosteric outside the ATP pocket (asciminib STAMP, trametinib MEK); Type IV substrate-mimetic; covalent (afatinib, osimertinib, ibrutinib).

Kinome groups (Manning)

GroupMembersExamples
TK (tyrosine)90EGFR/HER family, ABL, SRC family, JAK1–3 + TYK2, ALK, ROS1, RET, KIT, FLT3, BTK, ITK, BMX, TEC, FGFR1–4, VEGFR1–3, MET, NTRK1–3, AXL, MERTK, TYRO3, DDR1/2, EPH receptors
TKL (tyrosine-kinase-like)43RAF (ARAF, BRAF, CRAF), MLK, LRRK2, IRAK1–4, ALK1–7 (TGFβ family)
STE47MAPK cascade scaffolds; MEK1/2 (MAP2K1/2), MKK3/6, MKK4/7, MST, PAK
CK112CK1α/δ/ε; circadian; recruited to E3 by lenalidomide (Krönke 2014)
AGC63PKA, PKB/AKT1–3, PKC isoforms, S6K1/2, ROCK1/2, SGK, PDK1, MSK
CAMK74CAMK1/2/4, AMPK α/β/γ, CHK1/2, MARK, DAPK, PIM
CMGC61CDK1–20, MAPK (ERK1/2 + p38 α/β/γ/δ + JNK1–3), GSK3α/β, CK2, DYRK, CLK
RGC5Receptor guanylate cyclases
Atypical40mTOR + ATM + ATR + DNA-PKcs + SMG1 + TRRAP (PIKK family); PDK, RIO; pseudokinases (~50 of total 518)

Approved kinase inhibitors — major

Counting drugs that hit a kinase as primary target; 2024 cumulative ≈ 85 small-molecule kinase inhibitors + ~25 kinase-targeted antibodies.

  • BCR-ABL (CML/Ph+ ALL) — imatinib Gleevec/Glivec Novartis (2001 first targeted oncology approval; Druker–Lydon–Talpaz–Sawyers; transformed CML); dasatinib Sprycel BMS (also SRC family); nilotinib Tasigna Novartis; bosutinib Bosulif Pfizer; ponatinib Iclusig Takeda/Ariad (active vs T315I gatekeeper); asciminib Scemblix Novartis 2021 (first STAMP = Specifically Targeting the ABL Myristoyl Pocket — allosteric; ASC4FIRST 2024 1L data)
  • EGFR (NSCLC) — gefitinib Iressa AZ + erlotinib Tarceva Roche/OSI (1st gen reversible); afatinib Giotrif BI + dacomitinib Vizimpro (2nd gen irreversible pan-HER); osimertinib Tagrisso AZ (3rd gen T790M+; FLAURA + FLAURA2 + ADAURA adjuvant; US6.5 B 2024); amivantamab Rybrevant J&J (EGFR × MET bispecific; MARIPOSA 2024 1L combo with lazertinib Leclaza Yuhan); aumolertinib (China); mobocertinib (exon 20 — withdrawn 2023); zipalertinib (exon 20 Cullinan/Taiho); HER2 lapatinib Tykerb, tucatinib Tukysa Seagen→Pfizer (HER2CLIMB); neratinib Nerlynx Puma; pyrotinib (China)
  • ALK / ROS1 / NTRK — crizotinib Xalkori Pfizer (1st-gen multi-kinase ALK/ROS1/MET); alectinib Alecensa Roche; brigatinib Alunbrig Takeda; ceritinib Zykadia Novartis; lorlatinib Lorbrena Pfizer (3rd-gen CNS-penetrant; CROWN 5-yr PFS); ensartinib (China); repotrectinib Augtyro BMS/Turning Point 2023 (ROS1/NTRK); entrectinib Rozlytrek Roche (ROS1/NTRK); larotrectinib Vitrakvi Bayer/Loxo (TRK first tissue-agnostic 2018); selpercatinib Retevmo Lilly/Loxo (RET, LIBRETTO); pralsetinib Gavreto Genentech/Blueprint (RET; commercial rights returned 2022); zenocutuzumab Bizengri Merus 2024 (NRG1 fusion bispecific)
  • VEGFR pan-tyrosine — sunitinib Sutent Pfizer; sorafenib Nexavar Bayer/Onyx; axitinib Inlyta Pfizer; cabozantinib Cabometyx/Cometriq Exelixis (also MET, AXL; RCC + HCC); lenvatinib Lenvima Eisai (TKR; CheckMate-9ER + LEAP combos with pembro); pazopanib Votrient GSK; regorafenib Stivarga Bayer; tivozanib Fotivda Aveo
  • BTK — ibrutinib Imbruvica AbbVie/J&J (covalent; ~US$4.3 B 2023 AbbVie share); acalabrutinib Calquence AZ (more selective; ECHO + AMPLIFY 2024 1L CLL combos); zanubrutinib Brukinsa BeiGene (BGB-3111; ALPINE head-to-head superiority vs ibrutinib in CLL — first Chinese-discovered drug to beat US-discovered comparator in registrational trial); pirtobrutinib Jaypirca Eli Lilly/Loxo (non-covalent reversible — overcomes C481S resistance; BRUIN-CLL-321 2024 head-to-head)
  • JAK / TYK2 — tofacitinib Xeljanz Pfizer (JAK1/3 — RA, UC, JIA; ORAL Surveillance MACE/cancer signal vs TNF); baricitinib Olumiant Lilly/Incyte (JAK1/2 — RA + AA alopecia 2022 + COVID-19); upadacitinib Rinvoq AbbVie (JAK1-selective — RA, PsA, AD, AS, UC, CD); ruxolitinib Jakafi/Jakavi Incyte/Novartis (JAK1/2 — MF, PV, acute + chronic GvHD; topical Opzelura for vitiligo + AD); fedratinib Inrebic BMS (MF); pacritinib Vonjo CTI (JAK2/IRAK1; thrombocytopenic MF); momelotinib Ojjaara/Omjjara GSK (MF + anemia); abrocitinib Cibinqo Pfizer (JAK1 — AD); ritlecitinib Litfulo Pfizer (JAK3/TEC AA); deucravacitinib Sotyktu BMS (TYK2 allosteric — pseudokinase JH2 domain — psoriasis 2022; first-in-class allosteric kinase)
  • CDK — palbociclib Ibrance Pfizer (CDK4/6; PALOMA; first CDK4/6 2015; US$5.2 B 2023); ribociclib Kisqali Novartis (NATALEE adjuvant 2024); abemaciclib Verzenio Lilly (monarchE EBC adjuvant); trilaciclib Cosela G1 (CDK4/6 for myeloprotection in ES-SCLC chemo); CDK4-selective PF-07220060 + atirmociclib Pfizer Phase III; CDK7 samuraciclib + XL-102 (Exelixis); CDK9 enitociclib + KB-0742 (Kronos); CDK2 BLU-222 + INX-315 (BMS)
  • PI3K — alpelisib Piqray Novartis (PI3Kα — SOLAR-1 PIK3CA-mut HR+ BC); inavolisib Itovebi Genentech 2024 (PI3Kα + degradation; INAVO120); copanlisib Aliqopa Bayer (i.v.; withdrawn US 2023); idelalisib Zydelig Gilead (PI3Kδ — CLL/iNHL; restricted use); duvelisib Copiktra Verastem (PI3Kδ/γ); umbralisib withdrawn; leniolisib Joenja Pharming (APDS PI3Kδ activating mutation 2023)
  • mTOR — everolimus Afinitor/Votubia/Zortress Novartis; sirolimus Rapamune Pfizer (rapamycin; transplant; LAM); temsirolimus Torisel Pfizer; ATP-competitive mTOR1/2 vistusertib + sapanisertib failed
  • MEK — trametinib Mekinist Novartis (1st MEK approval 2013; +dab combos); cobimetinib Cotellic Roche/Exelixis; binimetinib Mektovi Pierre Fabre/Array→Pfizer; selumetinib Koselugo AZ/Merck (NF1 plexiform neurofibroma 2020 — pediatric first NF1 approval)
  • BRAF — vemurafenib Zelboraf Roche (PLX4032; 2011; landmark BRAF V600E melanoma; Plexxikon scaffold-based discovery); dabrafenib Tafinlar Novartis; encorafenib Braftovi Pierre Fabre; pan-RAF + RAF dimers — tovorafenib Ojemda Day One 2024 (low-grade glioma pediatric Type II); naporafenib Erasca; exarafenib + ICP-189 (Innocare)
  • KRAS G12C — sotorasib Lumakras/Lumykras Amgen (AMG 510 — first approved KRAS inhibitor May 2021; CodeBreaK trials; covalent to C12 in switch-II pocket); adagrasib Krazati Mirati→BMS (MRTX849; KRYSTAL); divarasib Genentech GDC-6036 (RMC-6291 — Revolution Medicines tri-complex)
  • KRAS G12D — MRTX1133 Mirati/BMS, RMC-9805 Revolution Medicines; pan-KRAS RMC-6236 Phase III metastatic PDAC (RASolute 302)
  • FGFR — erdafitinib Balversa J&J (urothelial; THOR); pemigatinib Pemazyre Incyte (CCA FGFR2); futibatinib Lytgobi Taiho (irreversible covalent); infigratinib Truseltiq withdrawn; RLY-4008 lirafugratinib Relay (FGFR2-selective)
  • MET — capmatinib Tabrecta Novartis (METex14); tepotinib Tepmetko Merck KGaA; telisotuzumab vedotin Emrelis AbbVie 2024 ADC
  • Other — palbociclib partners; aurora AURK (alisertib MLN8237 Takeda Phase III); PLK1 (onvansertib Cardiff Oncology); WEE1 (adavosertib + zen-c3 zentalis + Debio 0123); CHK1/2 (prexasertib LY2606368 Lilly/Esperas); ATR (berzosertib Merck KGaA, elimusertib Bayer, camonsertib Repare/Roche, tuvusertib Mereo); ATM (M3541 + AZD0156); DNA-PK (peposertib Merck KGaA, BAY 2402234); CDK12/13 SR-4835 + INCB123667; menin revumenib Revuforj Syndax 2024 (KMT2A-r ALL/AML — landmark new mechanism); SOS1 BI-3406 + MRTX0902; SHP2 RMC-4630 + TNO155 + JAB-3068; ERK1/2 ulixertinib BVD-523 + LY3214996; PI4K3β + others

Allosteric (asciminib STAMP, deucravacitinib pseudokinase, RMC tri-complex); selective for specific mutations (osimertinib T790M, repotrectinib G2032R); covalent (third-gen + WRN helicase Vivace); degraders (BTK degraders NX-2127 Nurix, NX-5948; BCL-XL degraders Dialectic; CDK degraders Kymera); molecular glues (CRBN, VHL, DCAF1, DCAF15, DCAF16; Monte Rosa GSPT1).

Nuclear receptors

48-member superfamily (Mangelsdorf et al. 1995, Cell) with a conserved DBD (zinc-finger) + LBD (12 α-helix sandwich with AF-2 helix 12 that closes on agonist). Heterodimerise with RXR (Type II) or homodimerise (steroid Type I).

Steroid receptors

  • ER (estrogen) ERα/β
    • SERMs: tamoxifen Nolvadex AZ (1977 first targeted oncology); raloxifene Evista Lilly (osteoporosis); bazedoxifene + clomiphene + ospemifene
    • Aromatase inhibitors (cyp19A1; technically not NR drugs but pathway): anastrozole Arimidex, letrozole Femara, exemestane Aromasin
    • SERDs: fulvestrant Faslodex AZ (i.m. only); elacestrant Orserdu Stemline/Menarini 2023 (first oral SERD; ESR1-mutated HR+ BC); camizestrant AZ (SERENA-6 ctDNA-guided 2024 positive); giredestrant Roche (acelERA Phase III); imlunestrant Lilly (EMBER-3 head-to-head 2024); ARV-471 vepdegestrant Arvinas/Pfizer (PROTAC PROTEAC degrader; Phase III VERITAC-2 2024)
  • AR (androgen)
    • First-gen flutamide Eulexin, bicalutamide Casodex AZ, nilutamide
    • Second-gen: enzalutamide Xtandi Astellas/Pfizer (~US$5 B); apalutamide Erleada J&J (SPARTAN, TITAN); darolutamide Nubeqa Bayer (ARAMIS, ARASENS); proxalutamide; deucanidamide
    • CYP17 inhibitor abiraterone Zytiga J&J (LATITUDE); orteronel failed
    • AR degraders ARV-110 bavdegalutamide; ARV-766 luxdegalutamide Arvinas
  • PR (progesterone) — progestins (levonorgestrel, etonogestrel Nexplanon); ulipristal Ella + Esmya; mifepristone RU-486 Korlym (Cushing’s + termination)
  • GR (glucocorticoid) — endogenous cortisol; dexamethasone, prednisone/prednisolone, methylprednisolone, hydrocortisone, budesonide; selective: SEGRAs (selective glucocorticoid receptor agonists — vamorolone Agamree Catalyst 2023 DMD)
  • MR (mineralocorticoid) — endogenous aldosterone; spironolactone Aldactone, eplerenone Inspra, finerenone Kerendia Bayer 2021 (non-steroidal selective MRA; FIDELIO + FIGARO CKD-T2D; ~US$0.4 B 2023 → blockbuster trajectory); ocedurenone CIN-107 KBP

Vitamin / retinoid receptors

  • VDR (vitamin D) — calcitriol, paricalcitol Zemplar, doxercalciferol Hectorol; analogs for psoriasis (calcipotriol Dovonex)
  • RAR α/β/γ (retinoic acid) — all-trans-retinoic acid ATRA tretinoin Vesanoid (APL — landmark differentiation therapy; Wang Zhenyi 1986 Shanghai); isotretinoin Accutane (acne); adapalene Differin; bexarotene Targretin RXR-selective rexinoid
  • RXR α/β/γ — heterodimer partner; bexarotene; IRX4204 + RXR-selective

Metabolic / orphan receptors

  • PPARα — fibrates: fenofibrate Tricor, gemfibrozil Lopid, bezafibrate, pemafibrate Parmodia Kowa (Japan; PROMINENT US trial neutral 2022)
  • PPARγ — TZDs: pioglitazone Actos Takeda, rosiglitazone Avandia GSK (cardiovascular signal 2010; US restrictions lifted 2013); lobeglitazone (Korea); leriglitazone (X-ALD); pan-PPAR lanifibranor Phase III MASH
  • PPARδ — seladelpar Livdelzi CymaBay → Gilead 2024 (PBC); elafibranor Iqirvo Genfit/Ipsen 2024 (PBC; failed in MASH RESOLVE-IT)
  • LXR α/β (liver X) — cholesterol homeostasis; agonist VBL-104; LXRβ-selective
  • FXR (farnesoid X) — bile acid sensor; obeticholic acid Ocaliva Intercept (PBC 2016; rejected in MASH 2023 REGENERATE; bankruptcy 2023 → Alfasigma); cilofexor, tropifexor, vonafexor
  • CAR / PXR — xenobiotic; drug-drug interaction (PXR + CYP3A4 induction by rifampin, St John’s wort hyperforin)
  • THR α/β (thyroid) — endogenous T3/T4 (levothyroxine Synthroid); resmetirom Rezdiffra Madrigal 2024 (first FDA-approved MASH drug; THRβ-selective; MAESTRO-NASH; ~US$0.2 B run-rate end 2024)
  • ERR α/β/γ (estrogen-related) — orphan; metabolic research
  • ROR α/β/γt — Th17 differentiation; cintirorgon LYC-55716 + JNJ-61803534 (psoriasis); ROR antagonists for cancer
  • NR4A (NUR77/NURR1/NOR1) — orphan immediate-early; emerging targets
  • HNF4α / HNF1A — MODY genetics
  • REV-ERB α/β — circadian; SR9009 tool

Ion channels

~400 channels; classified by gating + ion selectivity. Comprehensive resource: IUPHAR Guide to Pharmacology.

Voltage-gated sodium (Nav)

Nine α-subunits Nav1.1–1.9 (SCN1A–SCN11A genes). Tetrodotoxin (TTX) sensitive vs resistant (Nav1.8/1.9 resistant).

  • Nav1.1 (SCN1A) — Dravet syndrome (loss-of-function); GEFS+
  • Nav1.2 (SCN2A) — neurodevelopmental disorders
  • Nav1.5 (SCN5A) — cardiac; LQT3 (gain), Brugada (loss); flecainide, mexiletine, ranolazine Ranexa (late Na current)
  • Nav1.7 (SCN9A) — pain; congenital insensitivity to pain (LOF); inherited erythromelalgia (GOF); failed selective inhibitors (PF-05089771, vixotrigine BIIB074, lacosamide unrelated)
  • Nav1.8 (SCN10A) — DRG-restricted; suzetrigine VX-548 Journavx Vertex 2025 (first non-opioid Nav1.8-selective acute pain; ~US$15.5 per pill; competitive vs opioids); also tested for diabetic neuropathic pain
  • Nav1.9 (SCN11A) — DRG; small-molecule efforts
  • Pan-Nav anticonvulsants — phenytoin Dilantin, carbamazepine Tegretol, lamotrigine Lamictal, oxcarbazepine Trileptal, eslicarbazepine Aptiom, lacosamide Vimpat (slow inactivation), valproate (mechanism complex), zonisamide Zonegran; antiarrhythmics class I (lidocaine, procainamide, flecainide)

Voltage-gated potassium (Kv) — >40 isoforms

  • Kv1 (Shaker family) Kv1.3 immune; dalazatide ShK-186 MS Phase I; Kv1.5 atrial-selective AF (vernakalant Brinavess Cipla; old)
  • Kv2 — neuronal
  • Kv4 — Ito cardiac
  • Kv7 (KCNQ1–5) — KCNQ1 cardiac LQT1; KCNQ2/3 epilepsy; ezogabine Potiga withdrawn 2017; XEN1101 azetukalner Xenon Phase III focal epilepsy 2024+
  • Kv11.1 (hERG, KCNH2) — antitarget; cardiac repolarisation; LQT2; dofetilide Tikosyn intentional class III antiarrhythmic; bsAfety screening
  • KCa (calcium-activated) — BKCa, SK1–3, IK1 (Gardos); andolast
  • Kir (inwardly rectifying) — Kir6.2/SUR1 = KATP — sulfonylureas (glipizide, glyburide, glimepiride; tolbutamide first 1956); meglitinides (repaglinide, nateglinide); diazoxide opener
  • K2P (two-pore) — TREK, TASK, TWIK — anaesthesia + pain research
  • Class III antiarrhythmics — amiodarone Cordarone (multi-channel), sotalol Betapace, dronedarone Multaq

Voltage-gated calcium (Cav)

L-type (Cav1.1–1.4 — CACNA1S/C/D/F), P/Q (Cav2.1 — CACNA1A), N (Cav2.2), R (Cav2.3), T-type (Cav3.1–3.3 — CACNA1G/H/I)

  • L-type dihydropyridines — amlodipine Norvasc Pfizer (#1 antihypertensive historically), nifedipine, felodipine, nicardipine, clevidipine Cleviprex i.v.; non-DHP verapamil Calan, diltiazem Cardizem
  • N-type — ziconotide Prialt Azur (ω-conotoxin synthetic; intrathecal severe chronic pain)
  • T-type — ethosuximide Zarontin (absence seizures); mibefradil withdrawn
  • α2δ subunit — gabapentin Neurontin Pfizer, pregabalin Lyrica Pfizer (~US$5 B at peak, generic 2019), mirogabalin Tarlige Daiichi Sankyo (Japan)

Ligand-gated (ionotropic) — cys-loop superfamily

  • nAChR nicotinic acetylcholine — varenicline Chantix/Champix Pfizer (α4β2 partial agonist smoking cessation), galantamine Razadyne (AD allosteric PAM); α7 — encenicline failed; α3β4 ganglionic
  • GABAA — benzodiazepines (diazepam Valium, lorazepam Ativan, alprazolam Xanax, midazolam Versed, clonazepam Klonopin); Z-drugs (zolpidem Ambien Sanofi, zopiclone/eszopiclone Lunesta, zaleplon); barbiturates (phenobarbital, thiopental); ethanol; propofol Diprivan; flumazenil reversal; zuranolone Zurzuvae Sage/Biogen 2023 (β3-selective; first oral PPD)
  • 5HT3 — ondansetron Zofran GSK, granisetron Kytril, palonosetron Aloxi, tropisetron, dolasetron Anzemet; alosetron Lotronex IBS-D restricted
  • Glycine receptor — strychnine
  • Cation iGluR — AMPA GRIA1–4 (perampanel Fycompa Eisai NCAM-AMPA epilepsy; LY451646 mibampator failed); positive allosteric modulators (PAMs) — aniracetam, CX1739; AMPA antagonist talampanel failed ALS
  • iGluR — kainate GRIK1–5 — selurampanel
  • iGluR — NMDA GRIN1 + GRIN2A–D + GRIN3A/B — non-competitive: ketamine Ketalar, esketamine Spravato J&J 2019 intranasal TRD (~US$0.6 B 2023); memantine Namenda Forest/Allergan (AD moderate); dextromethorphan/quinidine Nuedexta (PBA); dextromethorphan/bupropion Auvelity Axsome 2022 (depression); GluN2B-selective rislenemdaz CERC-301 + EVT 101; mGluR2/3 modulators above

TRP channels

  • TRPV1 capsaicin — capsaicin patch Qutenza Averitas, resiniferatoxin RTX Sorrento
  • TRPV4 — fluid; cystic fibrosis research
  • TRPM8 — menthol; cold
  • TRPA1 — pungent isothiocyanates; pain
  • TRPC, TRPP, TRPML

CFTR

The cystic fibrosis transmembrane regulator (ABC family; ATP-gated Cl⁻ channel). Vertex Pharmaceuticals CF franchise — total ~US11 B 2024:

  • ivacaftor Kalydeco 2012 (potentiator; gating mutations e.g. G551D)
  • lumacaftor/ivacaftor Orkambi 2015 (corrector + potentiator; F508del homozygous)
  • tezacaftor/ivacaftor Symdeko/Symkevi 2018
  • elexacaftor/tezacaftor/ivacaftor Trikafta/Kaftrio 2019 (~90 % of CF patients ≥ 6 years; F508del at least one allele)
  • vanzacaftor/tezacaftor/deutivacaftor Alyftrek 2024 next-gen
  • Competitive landscape: Sionna SION-451 + AbbVie ABBV-3067/2451 + Sionna/AbbVie pipeline; ARK Therapeutics; mRNA gene therapy Vertex VX-522 (lipid-NP-delivered CFTR mRNA Phase I), ReCode

Other channels

  • ENaC — amiloride; balcinrenone
  • ASIC — acid-sensing; A-317567
  • HCN — ivabradine Corlanor/Procoralan Servier/Amgen (heart rate)
  • Piezo1/2 — mechanotransduction (Patapoutian Nobel 2021); no drugs yet
  • Connexins / pannexins — research

Other major target classes

Proteases (~600-member degradome; Lopez-Otin & Bond 2008)

ClassDrug examples
ACElisinopril Prinivil, captopril Capoten (first 1981), enalapril Vasotec, ramipril Altace, perindopril, benazepril; ARNi sacubitril/valsartan Entresto
Reninaliskiren Tekturna (lacklustre)
Thrombin (FIIa)dabigatran Pradaxa BI; argatroban Acova; bivalirudin Angiomax; hirudin
Factor Xarivaroxaban Xarelto Bayer/J&J; apixaban Eliquis BMS/Pfizer (~US$13 B 2023 #1 anticoagulant); edoxaban Lixiana/Savaysa Daiichi Sankyo; betrixaban discontinued
Factor XIaabelacimab Anthos; milvexian BMS/J&J; asundexian Bayer (OCEANIC-AF stopped 2023 inferiority); osocimab Bayer
HIV proteasesaquinavir Invirase, indinavir Crixivan, ritonavir Norvir (boosting), lopinavir/ritonavir Kaletra, atazanavir Reyataz, darunavir Prezista (#1)
HCV NS3/4A proteasetelaprevir Incivek + boceprevir Victrelis (1st gen withdrawn); simeprevir Olysio (Janssen); paritaprevir (in Viekira); grazoprevir (Zepatier); glecaprevir (Mavyret AbbVie); voxilaprevir (Vosevi)
HCV NS5Adaclatasvir, ledipasvir (Harvoni Gilead), ombitasvir, elbasvir, velpatasvir (Epclusa), pibrentasvir (Mavyret)
HCV NS5B polymerasesofosbuvir Sovaldi Gilead 2013 (US$84,000 12-week course — sparked drug-pricing debate); dasabuvir
SARS-CoV-2 Mpro (3CLpro)nirmatrelvir/ritonavir Paxlovid Pfizer 2021; ensitrelvir Xocova Shionogi (Japan 2022); FB2001; bofutrelvir
DPP-4sitagliptin Januvia Merck (first 2006); saxagliptin Onglyza; linagliptin Tradjenta; alogliptin Nesina; vildagliptin (not US); teneligliptin
Neprilysinsacubitril (prodrug LBQ657 active) component of Entresto
BACE1 (β-secretase)atabecestat J&J + verubecestat Merck + lanabecestat AZ — all failed AD Phase III worsened cognition; abandoned class
γ-secretasesemagacestat (worsened) + avagacestat — failed AD; Notch-inhibitors crenigacestat + nirogacestat Ogsiveo SpringWorks 2023 (desmoid tumours — different indication)
MMPsbroad failures historic; selective MMP-9 andecaliximab failed gastric; MMP-12 + ADAM10/17
Calpain / cathepsin Kodanacatib withdrawn cardiovascular; calpain in research
Proteasomebortezomib Velcade Takeda/Millennium 2003 (first; multiple myeloma); carfilzomib Kyprolis Amgen; ixazomib Ninlaro Takeda (oral)

DPP-4 inhibitors

(See proteases above)

SGLT2 inhibitors

  • dapagliflozin Farxiga/Forxiga AstraZeneca (DAPA-HF, DAPA-CKD, DELIVER); ~US$5 B 2023
  • empagliflozin Jardiance BI/Lilly (EMPA-REG OUTCOME 2015 — first CV outcome trial showing CV-death reduction in T2DM and shifted entire diabetes field; EMPEROR-Reduced + Preserved HFrEF + HFpEF; EMPA-KIDNEY); ~US$9 B 2023
  • canagliflozin Invokana J&J (amputation signal earlier); CANVAS, CREDENCE
  • ertugliflozin Steglatro Merck/Pfizer
  • bexagliflozin Brenzavvy TheracosBio 2023
  • sotagliflozin Inpefa Lexicon (SGLT1/2 dual; heart failure 2023)

PCSK9

  • alirocumab Praluent Sanofi/Regeneron
  • evolocumab Repatha Amgen (FOURIER + FOURIER-OLE)
  • inclisiran Leqvio Novartis (siRNA twice yearly; ORION trials; ~US4.5 B)
  • oral small molecules — MK-0616 enlicitide Merck Phase III; AZD0780 + lerodalcibep LIB003 Lib Therapeutics; PCSK9 vaccines preclinical

Bcl-2 family

  • venetoclax Venclexta/Venclyxto AbbVie/Genentech (CLL + AML; MURANO, CLL14, VIALE-A); ~US$2.3 B 2023
  • BCL-XL — pelcitoclax APG-1252 Ascentage; DT2216 PROTAC
  • MCL-1 — AZD5991, S64315 Servier (cardiac toxicity issues across class)

PARP

  • olaparib Lynparza AstraZeneca/MSD (first 2014 ovarian; SOLO + OlympiAD + PROfound + PROpel)
  • niraparib Zejula GSK/Tesaro (NOVA, PRIMA)
  • talazoparib Talzenna Pfizer (EMBRACA, TALAPRO-2 + 3)
  • rucaparib Rubraca Clovis (bankruptcy 2022; pharma& acquired)
  • fluzoparib (China Hengrui); pamiparib BeiGene

IDH

  • ivosidenib Tibsovo Servier (IDH1; AML, CCA; bought from Agios 2021)
  • enasidenib Idhifa BMS/Celgene (IDH2 AML; partnership ended)
  • vorasidenib Voranigo Servier 2024 (IDH1/2 dual; first oral for low-grade glioma IDH-mutant; INDIGO; CNS-penetrant — landmark glioma trial)
  • olutasidenib Rezlidhia Rigel (IDH1 AML 2022)

HDAC

  • vorinostat Zolinza Merck (CTCL; first HDACi 2006)
  • romidepsin Istodax Celgene/BMS
  • belinostat Beleodaq Spectrum→Acrotech
  • panobinostat Farydak Novartis (multiple myeloma; commercial discontinuation US 2021)
  • chidamide Epidaza Chipscreen (China selective HDAC1/2/3/10); tucidinostat
  • givinostat Duvyzat Italfarmaco 2024 (DMD — first non-steroidal)

Immune checkpoint (antibodies — also see Antibodies file)

  • PD-1: pembrolizumab Keytruda Merck (~US25 B 2023 — #1 drug globally; ~US29 B 2024; ~1,800 active trials); nivolumab Opdivo BMS; cemiplimab Libtayo Regeneron; dostarlimab Jemperli GSK; toripalimab Loqtorzi Junshi/Coherus; serplulimab Hetronifly Henlius; tislelizumab Tevimbra BeiGene/BMS; retifanlimab Zynyz Incyte; penpulimab AkesoBio/Sino Biopharm
  • PD-L1: atezolizumab Tecentriq Roche; durvalumab Imfinzi AZ (~US$4 B 2023); avelumab Bavencio Pfizer/Merck KGaA; envafolimab; sugemalimab; cosibelimab Checkpoint Therapeutics 2024
  • CTLA-4: ipilimumab Yervoy BMS; tremelimumab Imjudo AZ (combo with durva)
  • LAG-3: relatlimab Opdualag BMS (RELATIVITY-047 — first LAG-3 approval 2022)
  • TIGIT: tiragolumab Roche (multiple Phase III readouts; CITYSCAPE + SKYSCRAPER mixed); vibostolimab Merck; ociperlimab BeiGene; domvanalimab Arcus/Gilead
  • TIM-3: cobolimab GSK; sabatolimab Novartis (failed AML 2024); LY3321367
  • TIGIT × PD-1 bispecifics: rilvegostomig AZ; HLX301 Henlius
  • VISTA / B7-H3 / ICOS / OX40 / GITR / CD27 / CD47 — research/Phase II
  • CD47/SIRPα: magrolimab Forty Seven→Gilead failed AML 2024; lemzoparlimab; evorpacept ALX Oncology

Bispecific T-cell engagers (BiTEs / TCEs)

  • blinatumomab Blincyto Amgen (CD3 × CD19; pre-B ALL; first 2014); MEC-funded successor: BCMA × CD3
  • teclistamab Tecvayli J&J (BCMA × CD3 multiple myeloma; MajesTEC)
  • talquetamab Talvey J&J (GPRC5D × CD3; MM new target; MonumenTAL)
  • elranatamab Elrexfio Pfizer (BCMA × CD3; MagnetisMM)
  • epcoritamab Epkinly/Tepkinly AbbVie/Genmab (CD20 × CD3 DLBCL/FL); subcutaneous
  • glofitamab Columvi Roche (CD20 × CD3; 2:1 binding; fixed duration)
  • mosunetuzumab Lunsumio Roche (CD20 × CD3 FL)
  • linvoseltamab Lynozyfic Regeneron 2024 (BCMA × CD3)
  • tarlatamab Imdelltra Amgen 2024 (DLL3 × CD3 ES-SCLC; first half-life-extended BiTE in SCLC; DeLLphi trials; breakthrough indication)
  • mancozumab/anbenitamab Akeso (CLDN18.2)
  • catumaxomab Solitomab EpCAM × CD3 — historical
  • T-cell engagers across solid tumours: PRAME (IMA402 immatics, brenetafusp Immunocore), MAGE-A4 (afami-cel Tecelra Adaptimmune 2024 — first TCR-T; not BiTE but related); PSMA (acapatamab + JNJ-69086420 + xaluritamig); HER2 (zanidatamab Ziihera 2024 — biparatopic); STEAP1

ADCs (antibody-drug conjugates)

ADCTargetPayloadLinkerApproval
brentuximab vedotin AdcetrisCD30MMAEmc-vc-PABC (cleavable)Seagen→Pfizer 2011 HL/ALCL
trastuzumab emtansine Kadcyla T-DM1HER2DM1 (maytansine)MCC (non-cleavable)Roche 2013 BC adjuvant + metastatic
inotuzumab ozogamicin BesponsaCD22calicheamicinacid-labilePfizer ALL
gemtuzumab ozogamicin MylotargCD33calicheamicinacid-labilePfizer AML (withdrawn 2010, re-approved 2017)
polatuzumab vedotin PolivyCD79bMMAEmc-vcRoche DLBCL 2019
enfortumab vedotin PadcevNectin-4MMAEmc-vcAstellas/Seagen UC (EV-302 + pembro 1L)
trastuzumab deruxtecan Enhertu T-DXdHER2Dxd (exatecan derivative; DAR 8)tetrapeptide cleavableDaiichi Sankyo/AZ (DESTINY-Breast01–06; HER2-low and ultralow 2024) ~US$3.7 B 2024
sacituzumab govitecan TrodelvyTROP2SN-38 (irinotecan active)CL2A cleavableGilead/Immunomedics ($21 B 2020 acquisition) TNBC, HR+ BC, UC
tisotumab vedotin TivdakTFMMAEmc-vcGenmab/Seagen cervical
mirvetuximab soravtansine ElahereFRαDM4sulfo-SPDB cleavableAbbVie/ImmunoGen (US$10 B acquisition 2024) ovarian
loncastuximab tesirine ZynlontaCD19PBD-dimer (SG3199)mc-vcADC Therapeutics DLBCL
disitamab vedotin AidixiHER2MMAEmc-vcRemeGen (China) UC + gastric
datopotamab deruxtecan DatrowayTROP2DxdtetrapeptideDS/AZ 2025 BC (TROPION-Breast01)
patritumab deruxtecan HernexeosHER3DxdtetrapeptideDS/Merck (HER3-DXd) NSCLC 2025
sacituzumab tirumotecanTROP2TR-tecan—Kelun/Merck Phase III
ifinatamab deruxtecanB7-H3Dxd—DS/Merck SCLC
raludotatug deruxtecanCDH6Dxd—DS/Merck ovarian

Cell therapies — CAR-T + allo + gene therapy

DrugTargetIndicationCompanyList price (US)
tisagenlecleucel KymriahCD19r/r pALL, DLBCL, FLNovartis 2017US$475 k
axicabtagene ciloleucel YescartaCD19DLBCL, FL, iNHLGilead/Kite 2017US$420 k
brexucabtagene autoleucel TecartusCD19MCL, ALLGilead/KiteUS$420 k
lisocabtagene maraleucel BreyanziCD19DLBCL, CLL, FL, MCLBMS/JunoUS$489 k
idecabtagene vicleucel AbecmaBCMAMMBMS/2seventy bioUS$420 k
ciltacabtagene autoleucel CarvyktiBCMAMM (CARTITUDE 1L)J&J/LegendUS$465 k
obecabtagene autoleucel AucatzylCD19adult B-ALLAutolus 2024US$525 k
Allo CAR-T pipelinevarious—Allogene ALLO-501A + 715; CRISPR Therapeutics CTX112 + CTX121 (CRISPR-edited); Caribou CB-011; Cellectis UCART22; Wugen WU-CART-007—
Casgevy exa-cel (CRISPR/Cas9 ex vivo BCL11A enhancer)HbF reactivationSCD + β-thalVertex / CRISPR Therapeutics 2023 (first CRISPR-edited therapy approved)US$2.2 M
Lyfgenia lovo-celgene-addition LV BB305SCDBluebird Bio 2023US$3.1 M
Zynteglo beti-celβ-globinβ-thalBluebird 2022US$2.8 M
Skysona eli-celABCD1CALD (cerebral ALD)BluebirdUS$3.0 M
ZolgensmaSMN1 AAV9SMANovartis 2019 (single dose)US$2.1 M
LuxturnaRPE65 AAV2RPE65-mut RDSpark/Roche 2017US$0.85 M per eye
Hemgenix etranacogene dezaparvovecFIX AAV5Hemophilia BCSL Behring/uniQure 2022US$3.5 M
Roctavian valoctocogeneFVIII AAV5Hemophilia ABioMarin 2023US$2.9 M
Elevidys delandistrogenemicro-dystrophin AAVDMDSarepta 2023 (expanded 2024)US$3.2 M
Beqvez fidanacogeneFIXHemophilia BPfizer 2024US$3.5 M (later discontinued commercial 2025)
Vyjuvek beremagene geperpavecCOL7A1 HSV-1 topicalDEBKrystal Biotech 2023per-tube

PROTACs / molecular glues / TPD (targeted protein degradation)

  • ARV-471 vepdegestrant (ER PROTAC; Arvinas/Pfizer; Phase III)
  • ARV-110 bavdegalutamide (AR; discontinued); ARV-766 luxdegalutamide (AR; advancing)
  • KT-474 (IRAK4; Kymera/Sanofi)
  • NX-2127 + NX-5948 (BTK degraders; Nurix)
  • DT2216 (BCL-XL); CFT8634 (BRD9 — synovial sarcoma); CFT1946 (BRAF V600E)
  • BMS-986365 (AR); lenalidomide/pomalidomide/iberdomide/mezigdomide (cereblon CRBN molecular glues — IKZF1/3 degraders; mezigdomide Bristol-Myers 2024 myeloma)
  • Plinabulin tubulin (microtubule unrelated to degraders)
  • CRBN E3 glues: most clinical glues; DCAF15 indisulam → RBM39; VHL; DCAF1 + DCAF11 + DCAF16 emerging; DCAF11 Ribon NAMPT
  • Companies: Arvinas, Kymera, Foghorn, Monte Rosa, C4 Therapeutics, Vividion (BMS), Plexium, Captor, Halda, Frontier Medicines, Cullgen, Nurix, Ranok

Epigenetic targets — readers, writers, erasers

The “epigenome” druggable surface partitions cleanly: DNA methylation (writers DNMT1/3A/3B; eraser TET1–3 + readers MBD/UHRF), histone-tail methylation (writers PRC2/EZH2, DOT1L, NSD1–3, MLL/KMT2A–D, SETD2; erasers KDM1A/LSD1, KDM5A–D, KDM6A/UTX, KDM6B/JMJD3; readers PHD-finger ING, BAH, Tudor 53BP1, WD40 EED), histone-tail acetylation (writers HAT P300/CBP, GCN5/PCAF, MOZ, MORF; erasers HDAC classes I–IV; readers bromodomain BRD2/3/4/T, TRIM, BRPF), ubiquitylation (writers RING + HECT E3s; eraser DUBs USP/UCH/MJD/OTU/MINDY/ZUP1; readers UBA + UIM), SUMOylation (UBA2/AOS1 E1 → UBC9 E2 → SIZ/PIAS E3).

  • EZH2 (writer; PRC2 H3K27me3) — tazemetostat Tazverik Epizyme→Ipsen 2020 (epithelioid sarcoma INI1-loss + FL EZH2-mut)
  • DOT1L (writer; H3K79me) — pinometostat EPZ-5676 Epizyme failed MLL-r
  • BET (reader; BRD2/3/4 acetyl-lysine) — JQ1 (Bradner tool); molibresib I-BET762; mivebresib ABBV-075; CPI-0610 pelabresib Constellation→MorphoSys MF Phase III (MANIFEST-2); ZEN-3694 zinc Zentalis; INCB054329; ABBV-744 BD2-selective; PROTAC BET degraders ARV-825, dBET1, MZ1 + clinical FHD-609 FHD-286 Foghorn
  • HDAC — see main table (vorinostat, romidepsin, belinostat, panobinostat, givinostat, chidamide; selective HDAC6 ricolinostat ACY-1215 Acetylon + citarinostat ACY-241 + KA-2507 + tubastatin tool); class-IIa selective LBH589 (legacy panobinostat); HDAC3-selective RGFP966 tool
  • PRMT5 — pemrametostat GSK3326595 GSK; PF-06939999 Pfizer; JNJ-64619178; MTAP-synthetic-lethal PRMT5 AMG 193 Amgen, MRTX1719 Mirati, TNG908 Tango, PRT811 Prelude — selective for MTAP-deleted (CDKN2A locus co-del) tumours; one of hottest synthetic-lethal targets 2024–2025
  • WRN helicase — MSI-high synthetic lethality (Behan 2019); HRO761 Novartis (NCT05838768); VVD-133214 Vivace; HCBP01 + others
  • PRC2 EED inhibitor — EED226 Novartis tool; MAK683 clinical
  • G9a/GLP (EHMT1/2 writer H3K9me) — BIX-01294 tool; CM-272 + CM-579 (Madrid)
  • LSD1 / KDM1A — iadademstat ORY-1001 Oryzon (SCLC + AML); seclidemstat SP-2577 Salarius; bomedemstat IMG-7289 Imago/Merck (MF + PV); GSK2879552 failed
  • JMJD2 / KDM4 + JMJD3 / KDM6B — tool compounds
  • DNMT — azacitidine Vidaza / Onureg Otsuka-Celgene-BMS (azacitidine oral Onureg + injectable Vidaza; AML maintenance); decitabine Dacogen Otsuka + decitabine/cedazuridine Inqovi Astex/Otsuka oral 2020; guadecitabine SGI-110 failed
  • IDH1/2 + TET2 — IDH inhibitors restore epigenetic state (covered above)
  • Menin-KMT2A interaction — revumenib Revuforj Syndax 2024 first menin inhibitor (KMT2A-r ALL/AML); ziftomenib Kura (KOMET-001); bleximenib JNJ-75276617; enzomenib DSP-5336
  • CBP/EP300 (acetyltransferase) — CCS1477 inobrodib CellCentric (CRPC + AML); A485 + GNE-049 (BD2 + HAT) tools
  • NSD2 / WHSC1 (writer H3K36me) — KTX-1001 K36 (MM); various Phase I
  • SETD2 — EZM0414 KSQ Phase I MM
  • BAF / SWI-SNF complex — SMARCA2 BRM-selective degraders ACBI1 (Ciulli Tate); FHD-909 Foghorn (SMARCA4-null synthetic lethal); PRT3789 Prelude
  • AKR1C3 prodrug — nimorelin AST-3424

RNA-targeted small molecules + oligos

  • Splicing modulators (SF3B1, SMN2) — risdiplam Evrysdi Roche-PTC-SMA Foundation 2020 (SMN2 splicing; oral SMA paediatric + adult); branaplam Novartis discontinued HD
  • Antisense oligonucleotides (ASOs) — nusinersen Spinraza Ionis-Biogen (SMA SMN2 splice; intrathecal); inotersen Tegsedi Ionis (hATTR; nephrotoxic); volanesorsen Waylivra Ionis (FCS); mipomersen Kynamro (FH; withdrawn); inclisiran (siRNA technically — PCSK9 above); milasen one-patient Batten n-of-1 (Kim 2019)
  • siRNA / GalNAc-siRNA — patisiran Onpattro Alnylam-Sanofi (TTR LNP); vutrisiran Amvuttra Alnylam (TTR GalNAc q3-mo s.c.); inclisiran Leqvio Novartis (PCSK9 GalNAc); givosiran Givlaari Alnylam (AIP ALAS1); lumasiran Oxlumo Alnylam (PH1 HAO1); nedosiran Rivfloza Novo (PH1/2/3 LDHA); fitusiran Qfitlia Sanofi (Hemophilia A/B AT)
  • mRNA therapeutics — Moderna mRNA-1010 flu, mRNA-1083 flu/COVID combo, mRNA-1647 CMV, mRNA-1273.815 COVID JN.1; Moderna + Merck individualised mRNA-4157/V940 melanoma adjuvant Phase III; BioNTech BNT122 (autogene cevumeran pancreatic, INDIVIDUALISED), BNT111 melanoma fixed; CureVac mRNA flu KO
  • CRISPR therapeutics — Casgevy (above); Editas EDIT-301; Intellia NTLA-2001 in-vivo TTR (Phase III MAGNITUDE) + NTLA-2002 hereditary angioedema (Phase III HAELO); Beam BEAM-101 base-editing SCD; Verve VERVE-102 PCSK9 (LDL-C lowering); Prime Editing — PE7 (Liu 2024); Tessera Gene Writing; Tome SCALE

Adjacent

Graph View

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