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TitleCDK2 heterobifunctional degraders co-degrade CDK2 and cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancers.
Journal, issue, pagesCell Chem Biol, Vol. 32, Issue 4, Page 556-569.e24, Year 2025
Publish dateApr 17, 2025
AuthorsNicholas Kwiatkowski / Tong Liang / Zhe Sha / Philip N Collier / Annan Yang / Murugappan Sathappa / Atanu Paul / Lijing Su / Xiaozhang Zheng / Robert Aversa / Kunhua Li / Revonda Mehovic / Christina Kolodzy / Susanne B Breitkopf / Dapeng Chen / Charles L Howarth / Karen Yuan / Hakryul Jo / Joseph D Growney / Matthew Weiss / Juliet Williams /
PubMed AbstractCCNE1 amplification drives aberrant CDK2-cyclin E1 activity in cancer. Despite activity of CDK2 inhibitors, their therapeutic margins are limited by poor CDK selectivity. We developed a degrader with ...CCNE1 amplification drives aberrant CDK2-cyclin E1 activity in cancer. Despite activity of CDK2 inhibitors, their therapeutic margins are limited by poor CDK selectivity. We developed a degrader with high selectivity for CDK2 over CDK1 that also unexpectedly led to cyclin E1 degradation and potent and complete suppression of RB phosphorylation at concentrations with low CDK2 occupancy and negligible CDK1 degradation. Co-depletion of CDK2 and cyclin E1 also resensitized palbociclib-adapted breast cancer cells to cell cycle blockade. Overall, the improved potency and selectivity of the degrader for CDK2 over small-molecule inhibitors drives antiproliferative activity with greater specificity for CCNE1 cancer cells and RB dependency. Using an orally administered degrader, we demonstrate deep and sustained RB pathway suppression, which is needed to induce stasis in CCNE1 tumors. These results highlight the potential of this modality to target CDK2 potently and selectivity in this biomarker-defined patient population with high unmet need.
External linksCell Chem Biol / PubMed:40250405
MethodsEM (single particle) / X-ray diffraction
Resolution2.54 - 2.95 Å
Structure data

46464

9d0w

EMDB-46464, PDB-9d0w:
Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 4
Method: EM (single particle) / Resolution: 2.95 Å

46465

9d0x

EMDB-46465, PDB-9d0x:
Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 4 (local mask)
Method: EM (single particle) / Resolution: 2.84 Å

PDB-9d0u:
Crystal structure of CDK2 in complex with Cpd 2
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

PDB-9d0v:
Crystal structure of CDK2/CyclinE1 in complex with Cpd 2
Method: X-RAY DIFFRACTION / Resolution: 2.54 Å

Chemicals

PDB-1a1h:
QGSR (ZIF268 VARIANT) ZINC FINGER-DNA COMPLEX (GCAC SITE)

ChemComp-HOH:
WATER

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER

ChemComp-GOL:
GLYCEROL

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-ZN:
Unknown entry

PDB-1a1i:
RADR (ZIF268 VARIANT) ZINC FINGER-DNA COMPLEX (GCAC SITE)

Source
  • homo sapiens (human)
KeywordsCELL CYCLE / kinase / degrader / inhibitor / CDK2 / ternary complex

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