Degraders and molecular glues
A ligand for the target, a recruiter for an E3 ligase, and a cell that does the rest: the protein is tagged and destroyed rather than blocked. Cereblon is the ligase almost everything uses today. The grid below is target against e3 ligase: 7 by 1 from 14 medicines, 4 combinations approved, 3 in development, 0 tried and stopped, 3 untried in this corpus.
Every tried combination
| Medicines | Records | Stopped, and why | |||||||
|---|---|---|---|---|---|---|---|---|---|
| IKZF1 x IKZF3 | Cereblon (CRBN) | Approved | 3 | 2 | 0 | - | |||
| Androgen receptor | E3 ligase not recorded | In development | 0 | 3 | 0 | - | |||
| BTK (Bruton tyrosine kinase) | E3 ligase not recorded | In development | 0 | 2 | 0 | - | |||
| ALK | Cereblon (CRBN) | In development | 0 | 1 | 0 | - | |||
| Estrogen receptor (ERα) | Cereblon (CRBN) | Approved | 1 | 0 | 0 | - | |||
| IKZF1 (Ikaros) | Cereblon (CRBN) | Approved | 1 | 0 | 0 | - | |||
| PIK3CA / PI3K-alpha | E3 ligase not recorded | Approved | 1 | 0 | 0 | - |
Stopped, and why
0 medicines recorded as stopped; 0 recorded reasons, including stopped studies of medicines still in developmentNo stopped study, withdrawn approval or negative result is recorded for a medicine in this format.
Proposed, not yet tried
5 proposals from the open pipeline, scored and searched (docs/OPEN-PIPELINE.md); hypotheses, not records of a medicine| Score | Target | E3 ligase | Status | Rationale | Evidence | Now in the corpus |
|---|---|---|---|---|---|---|
| 85 | KRAS | Cereblon (CRBN) | Preclinical | KRAS degrader recruiting cereblon. 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.Proposed by OnCo open pipeline, searched 2026-09-23. | Untried | |
| 81 | EGFR | Cereblon (CRBN) | Clinical evidence | EGFR degrader recruiting cereblon. 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.Proposed by OnCo open pipeline, searched 2026-09-23. | Untried | |
| 80 | BRAF | Cereblon (CRBN) | Clinical evidence | BRAF degrader recruiting cereblon. 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.Proposed by OnCo open pipeline, searched 2026-09-23. | Untried | |
| 65 | Estrogen receptor (ERα) | VHL | Preclinical | Estrogen receptor (ERα) degrader recruiting VHL. 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.Proposed by OnCo open pipeline, searched 2026-09-23. | Untried | |
| 64 | MDM2 | Cereblon (CRBN) | Clinical evidence | MDM2 degrader recruiting cereblon. 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.Proposed by OnCo open pipeline, searched 2026-09-23. | Untried |
Not placed
1 of 15 medicines in this format (7%)These medicines belong to the format but their target is on no record the engine reads: the targets field is empty, the target lists no such drug, the trials linked to it name no target of its own, and the modality, mechanism and summary text name none the corpus knows. They are listed here rather than placed by guesswork; adding the target to the record puts them in the grid on the next build.
How this grid is read from the records
Each medicine's parts come from its own record: the targets field first, else the target records that list the medicine, else a sibling conjugate that shares its antibody name, else the trials linked to it, else the target names the corpus knows found in its modality, mechanism or summary text. The E3 ligase is read from the mechanism and modality text (cereblon for CELMoDs, IMiDs and most PROTACs, VHL where stated); a degrader whose text names no ligase is shown as not recorded. Every part carries the fields it was read from and a confidence in the JSON file.
What the states mean, and do not
Approved: a medicine in the cell has an approval row or a regulator's approved entry and is not recorded as withdrawn. In development: a recruiting, active or planned trial, a development-phase record status, or active studies in the ClinicalTrials.gov index, and no approval. Tried and stopped: every medicine in the cell is withdrawn, negative or historic, or its only trial evidence is a terminated, withdrawn or negative study, or its approval was withdrawn. Untried: no medicine in this corpus combines the two parts.
A cell is coloured by its strongest medicine; the table shows each medicine with its own state. The reasons quoted under Stopped, and why are the records' words, including the registry's whyStopped text where the sponsor wrote one, and include stopped studies of medicines that are still in development elsewhere. Nothing here is medical advice.