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2008","href":"https://products.mhra.gov.uk/?search=Thalidomide"},{"record":"thalidomide","field":"regional.JP","kind":"regional","state":"approved","label":"PMDA / MHLW (JP): approved 2008","href":"https://www.pmda.go.jp/english/review-services/reviews/approved-information/drugs/0002.html"},{"record":"thalidomide","field":"regional.AU","kind":"regional","state":"approved","label":"TGA (PBS for reimbursement) (AU): approved","href":"https://www.tga.gov.au/resources/artg?search_api_views_fulltext=Thalomid"},{"record":"registry:thalidomide","kind":"registry","state":"development","label":"ClinicalTrials.gov: 6 recruiting, active or planned studies (fetched 2026-09-21)","href":"/drugs/thalidomide/#registry"}],"reasons":[]},{"id":"tri-611","name":"TRI-611","route":"/drugs/tri-611/","status":"phase-2","modality":"protein degrader","state":"development","confidence":"high","fields":["targets","modality","mechanism"],"components":{"target":{"id":"alk","name":"ALK","href":"/targets/alk/","confidence":"high","from":["targets"],"detail":null},"ligase":{"id":"cereblon","name":"Cereblon (CRBN)","href":"/targets/cereblon/","confidence":"high","from":["modality","mechanism"],"detail":null},"degraderType":{"id":"molecular-glue","name":"Molecular glue","href":"/technologies/celmods/","confidence":"high","from":["modality","mechanism"],"detail":null}},"evidence":[{"record":"tri-611","field":"status","kind":"drug","state":"development","label":"Drug record status: phase 2","href":"/drugs/tri-611/"},{"record":"nct07491497","field":"status","kind":"trial","state":"development","label":"A Phase 1/2 Study of TRI-611 in ALK-Positive NSCLC: phase 1/2, recruiting","href":"/trials/nct07491497/"},{"record":"registry:tri-611","kind":"registry","state":"development","label":"ClinicalTrials.gov: 1 recruiting, active or planned study (fetched 2026-09-21)","href":"/drugs/tri-611/#registry"}],"reasons":[]},{"id":"vepdegestrant","name":"Vepdegestrant","route":"/drugs/vepdegestrant/","status":"approved","modality":"PROTAC oestrogen receptor degrader","state":"approved","confidence":"high","fields":["targets","modality","mechanism"],"components":{"target":{"id":"estrogen-receptor","name":"Estrogen receptor (ERα)","href":"/targets/estrogen-receptor/","confidence":"high","from":["targets"],"detail":null},"ligase":{"id":"cereblon","name":"Cereblon (CRBN)","href":"/targets/cereblon/","confidence":"high","from":["modality","mechanism"],"detail":null},"degraderType":{"id":"protac","name":"PROTAC (heterobifunctional)","href":"/technologies/protac-degrader/","confidence":"high","from":["modality","mechanism"],"detail":null}},"evidence":[{"record":"vepdegestrant","field":"status","kind":"drug","state":"approved","label":"Drug record status: approved","href":"/drugs/vepdegestrant/"},{"record":"vepdegestrant","field":"approvals[0]","kind":"approval","state":"approved","label":"US 2026: ESR1-mutated ER+/HER2- advanced or metastatic breast cancer after endocrine therapy","href":"/drugs/vepdegestrant/"},{"record":"vepdegestrant","field":"regional.US","kind":"regional","state":"approved","label":"FDA (US): approved 2026","href":"/regulatory/regions/"},{"record":"nct06206837","field":"status","kind":"trial","state":"development","label":"A Study to Learn About Vepdegestrant When Given With PF-07220060 to People With Advanced or Metastatic Breast Cancer.: phase 1/2, active","href":"/trials/nct06206837/"},{"record":"nct04606446","field":"status","kind":"trial","state":"development","label":"Study of PF-07248144 in Advanced or Metastatic Solid Tumors: phase 2, recruiting","href":"/trials/nct04606446/"},{"record":"nct05548127","field":"status","kind":"trial","state":"development","label":"TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study A): phase 1/2, active","href":"/trials/nct05548127/"},{"record":"nct05573555","field":"status","kind":"trial","state":"development","label":"TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study B): phase 1/2, active","href":"/trials/nct05573555/"},{"record":"nct06125522","field":"status","kind":"trial","state":"development","label":"TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer. (Sub-Study C): phase 1/2, active","href":"/trials/nct06125522/"},{"record":"nct05909397","field":"status","kind":"trial","state":"development","label":"Vepdegestrant (ARV-471/PF-07850327) + Palbociclib vs Letrozole + Palbociclib in ER(+)/HER2(-) Advanced Breast Cancer: phase 3, active","href":"/trials/nct05909397/"},{"record":"registry:vepdegestrant","kind":"registry","state":"development","label":"ClinicalTrials.gov: 8 recruiting, active or planned studies (fetched 2026-09-21)","href":"/drugs/vepdegestrant/#registry"}],"reasons":[]}],"unresolved":[{"id":"rnk05047","name":"RNK05047","route":"/drugs/rnk05047/","format":"degrader","modality":"Targeted protein degrader","missing":["target","ligase"],"why":"No target on the record: the targets field is empty and the modality and mechanism text name none the corpus knows."}],"stopped":[],"proposed":[{"id":"deg-kras-cereblon","format":"degrader","name":"KRAS degrader recruiting cereblon","a":"kras","b":"cereblon","raw":{"a":"kras","b":"cereblon"},"matched":true,"unmatched":[],"rationale":"KRAS is validated by two approved G12C inhibitors (sotorasib, adagrasib) and cereblon is the E3 ligase of every approved degrader in the corpus (lenalidomide, vepdegestrant). No corpus degrader targets KRAS, and the search found that the KRAS G12D degrader now in phase 3 recruits VHL rather than cereblon, so the KRAS x cereblon cell is open while the target itself is clinically validated for degradation. KRAS inhibitors are limited to one mutant (G12C) and to the inactive state, while a degrader removes the protein whatever nucleotide it holds; degradation of KRAS G12D is now proven in patients with a VHL-recruiting molecule, so the open question is whether cereblon gives better exposure or a different resistance profile.","caveat":"A degrader still needs a mutant-selective binder, which for G12D exists only in a few chemotypes; and a cereblon-recruiting version would have to justify itself against a VHL-recruiting molecule already in phase 3.","status":"preclinical evidence","statusLabel":"Preclinical","score":{"total":85,"burden":35,"worldDeaths":3188897,"validationA":15,"validationB":15,"plausibility":20},"evidence":[{"label":"Paper: Jiang L et al. (2026-08-15)","url":"https://doi.org/10.1016/j.ejps.2026.107633","quote":"Discovery of a Potent and Selective KRAS G12D Degrader based on PROTAC Degradation.","kind":"paper"},{"label":"Paper: Ji X et al. (2026-08-01)","url":"https://doi.org/10.1021/acs.jmedchem.6c01832","quote":"Discovery and Characterization of RP04340: A Highly Potent and Orally Active Pan-KRAS PROTAC Degrader.","kind":"paper"},{"label":"Trial: Astellas Pharma Global Development, Inc. (2026-05-04), neighbouring cell","url":"https://clinicaltrials.gov/study/NCT07566052","quote":"A Study to Compare Setidegrasib (ASP3082) With Docetaxel, in People With Non-small Cell Lung Cancer With a KRAS G12D Mutation","kind":"trial","adjacent":true},{"label":"Paper: Yoshinari T et al. (2025-08-23), neighbouring cell","url":"https://doi.org/10.1038/s42004-025-01662-4","quote":"Herein, we report the discovery and characterization of ASP3082, a KRAS(G12D)-selective degrader, and the crystal structure of the drug-induced ternary complex of KRAS(G12D)/ASP3082/VHL (von Hippel-Lindau).","kind":"paper","adjacent":true}],"refs":["adagrasib","lenalidomide","sotorasib","vepdegestrant"],"cancers":["pancreatic","colorectal","kras-g12c-nsclc","kras-g12c-pdac"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"deg-egfr-cereblon","format":"degrader","name":"EGFR degrader recruiting cereblon","a":"egfr","b":"cereblon","raw":{"a":"egfr","b":"cereblon"},"matched":true,"unmatched":[],"rationale":"EGFR is validated by kinase inhibitors and antibodies (osimertinib, amivantamab, cetuximab) and cereblon is the E3 ligase of every approved degrader in the corpus (lenalidomide, pomalidomide, vepdegestrant). No corpus degrader targets EGFR, although the corpus records the C797S resistance problem that inhibitors cannot solve and degraders can. Osimertinib resistance often runs through C797S and kinase-independent scaffolding functions of EGFR, which inhibitors cannot touch but a degrader removes; wild-type EGFR degradation in skin and gut is the selectivity problem, so mutant-selective degraders are the design in play.","caveat":"A degrader that removes wild-type EGFR would reproduce cetuximab's skin and gut toxicity with no off switch; mutant selectivity is a requirement, not a nicety.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":81,"burden":33,"worldDeaths":1817469,"validationA":15,"validationB":15,"plausibility":18},"evidence":[{"label":"Trial: Haisco Pharmaceutical Group Co., Ltd. (2023-09-22)","url":"https://clinicaltrials.gov/study/NCT06050980","quote":"This is a phase I, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, PK and PD of HSK40118 when given orally in patients with active EGFR mutation locally advanced or metastatic non-small cell lung cancer (NSCLC).","kind":"trial"}],"refs":["amivantamab","cetuximab","lenalidomide","osimertinib","pomalidomide","vepdegestrant"],"cancers":["egfr-mutant-nsclc","nsclc"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"deg-braf-cereblon","format":"degrader","name":"BRAF degrader recruiting cereblon","a":"braf","b":"cereblon","raw":{"a":"braf","b":"cereblon"},"matched":true,"unmatched":[],"rationale":"BRAF is validated by three approved inhibitors (dabrafenib, encorafenib, vemurafenib) and cereblon by every approved degrader in the corpus (lenalidomide, vepdegestrant). No corpus degrader targets BRAF, although the dimer-mediated resistance the corpus records for BRAF inhibitors is exactly what removal of the protein addresses. BRAF inhibitors fail through dimer-dependent reactivation, which a degrader avoids by removing the protein; class I mutant selectivity over wild-type BRAF and CRAF is needed to avoid the paradoxical activation and skin toxicity of first-generation inhibitors.","caveat":"Colorectal BRAF V600E disease resists BRAF blockade through EGFR feedback, which a degrader does not remove; the degrader would still need an EGFR antibody partner there.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":80,"burden":34,"worldDeaths":2780155,"validationA":15,"validationB":15,"plausibility":16},"evidence":[{"label":"Trial: C4 Therapeutics, Inc. (2022-12-30)","url":"https://clinicaltrials.gov/study/NCT05668585","quote":"The purpose of this study is to evaluate the safety and tolerability of CFT1946 as well as to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of CFT1946 as monotherapy (Arm A) and in combination with trametinib (CFT1946 + trametinib; Arm B) or Cetuximab (CFT1946 + cetuximab; Arm C).","kind":"trial"},{"label":"Paper: Ohoka N et al. (2022-06-05)","url":"https://doi.org/10.1111/cas.15401","quote":"Development of a potent small-molecule degrader against oncogenic BRAF<sup>V600E</sup> protein that evades paradoxical MAPK activation.","kind":"paper"}],"refs":["dabrafenib","encorafenib","lenalidomide","vemurafenib","vepdegestrant"],"cancers":["braf-v600-melanoma","braf-v600e-colorectal","braf-v600e-nsclc"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"deg-estrogen-receptor-vhl","format":"degrader","name":"Estrogen receptor (ERα) degrader recruiting VHL","a":"estrogen-receptor","b":"vhl","raw":{"a":"estrogen-receptor","b":"vhl"},"matched":false,"unmatched":["vhl"],"rationale":"The oestrogen receptor is the only target in the corpus with an approved heterobifunctional degrader (vepdegestrant) alongside approved SERDs (fulvestrant, elacestrant). All corpus degraders recruit cereblon, so an oestrogen receptor x VHL degrader is an untried cell on the E3 axis. The approved ER degrader (vepdegestrant) recruits cereblon; ESR1-mutant disease responds to it, but cereblon-pathway resistance would leave no degrader option, so a VHL-recruiting ER degrader is the natural second axis, and VHL now has a degrader in phase 3 on another target.","caveat":"There is no clinical evidence yet that cereblon-pathway resistance limits vepdegestrant; the proposal is a hedge whose value depends on that resistance appearing.","status":"preclinical evidence","statusLabel":"Preclinical","score":{"total":65,"burden":28,"worldDeaths":666103,"validationA":15,"validationB":10,"plausibility":12},"evidence":[{"label":"Paper: Zhang X et al. (2022-10-12)","url":"https://doi.org/10.1021/acsptsci.2c00109","quote":"Therefore, we designed a nucleic acid-conjugated PROTAC, ERE-PROTAC, via a click reaction, in which the ERE sequence recruits ERα and the typical small molecule VH032 recruits the von Hippel-Lindau (VHL) E3 ligase.","kind":"paper"},{"label":"Paper: Zhou Z et al. (2023-11-08)","url":"https://doi.org/10.1016/j.bmc.2023.117526","quote":"Here, we designed a GSH-responsive ERα PROTAC, which is generated by conjugating an o-nitrobenzenesulfonyl group to the hydroxyl group of VHL-based ERα PROTAC through a nucleophilic substitution reaction.","kind":"paper"}],"refs":["elacestrant","fulvestrant","vepdegestrant"],"cancers":["breast-hr-positive","hr-positive-metastatic-post-cdk46"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"},{"id":"deg-mdm2-cereblon","format":"degrader","name":"MDM2 degrader recruiting cereblon","a":"mdm2","b":"cereblon","raw":{"a":"mdm2","b":"cereblon"},"matched":true,"unmatched":[],"rationale":"MDM2 is validated by inhibitors in phase 3 (brigimadlin) and cereblon by every approved degrader in the corpus (lenalidomide, vepdegestrant). No corpus degrader targets MDM2, though the feedback stabilisation that limits MDM2 inhibitors is a textbook case for degradation. MDM2 inhibitors free p53 but also stabilise MDM2 by feedback, blunting the response; a degrader removes MDM2 and the feedback with it, giving deeper p53 activation, at the price of the same on-target thrombocytopenia and gut toxicity.","caveat":"Thrombocytopenia and gut toxicity from p53 activation in normal tissue limited MDM2 inhibitors; a degrader that activates p53 harder may hit the same wall unless dosed intermittently.","status":"clinical evidence","statusLabel":"Clinical evidence","score":{"total":64,"burden":25,"worldDeaths":305405,"validationA":10,"validationB":15,"plausibility":14},"evidence":[{"label":"Trial: Kymera Therapeutics, Inc. (2023-03-20)","url":"https://clinicaltrials.gov/study/NCT05775406","quote":"This Phase 1 study will evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and clinical activity of KT-253 in adult patients with relapsed or refractory (R/R) high grade myeloid malignancies, acute lymphocytic leukemia (ALL), R/R lymphoma, myelofibrosis, and R/R solid tumors.","kind":"trial"},{"label":"Paper: Kandarpa M et al. (2026-04-15)","url":"https://doi.org/10.1038/s41375-026-02957-8","quote":"Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models.","kind":"paper"}],"refs":["brigimadlin","lenalidomide","vepdegestrant"],"cancers":["aml","liposarcoma","mds"],"proposedBy":"OnCo open pipeline","on":"2026-09-23"}],"note":"Every state is derived from the records named in evidence; untried means no medicine in this corpus combines the two parts. Proposed cells are hypotheses from the open pipeline (docs/OPEN-PIPELINE.md), not records of a medicine. CC BY-NC 4.0, attribute Data from OnCo (onco.cc). Not medical advice."}