2. Academic Validation
  3. CDK2 heterobifunctional degraders co-degrade CDK2 and cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancers

CDK2 heterobifunctional degraders co-degrade CDK2 and cyclin E resulting in efficacy in CCNE1-amplified and overexpressed cancers

  • Cell Chem Biol. 2025 Apr 17;32(4):556-569.e24. doi: 10.1016/j.chembiol.2025.03.006.
Nicholas Kwiatkowski 1,  Tong Liang 1,  Zhe Sha 1,  Philip N Collier 1,  Annan Yang 1,  Murugappan Sathappa 1,  Atanu Paul 1,  Lijing Su 1,  Xiaozhang Zheng 1,  Robert Aversa 1,  Kunhua Li 1,  Revonda Mehovic 1,  Christina Kolodzy 1,  Susanne B Breitkopf 1,  Dapeng Chen 1,  Charles L Howarth 1,  Karen Yuan 1,  Hakryul Jo 1,  Joseph D Growney 1,  Matthew Weiss 1,  Juliet Williams 2
Affiliations

Affiliations

  • 1 Kymera Therapeutics, Inc., Biological Sciences, 500 North Beacon St. 4th Floor, Watertown, MA 02472, USA.
  • 2 Kymera Therapeutics, Inc., Biological Sciences, 500 North Beacon St. 4th Floor, Watertown, MA 02472, USA. Electronic address: jwilliams@kymeratx.com.
PMID: 40250405 DOI: 10.1016/j.chembiol.2025.03.006
Abstract

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 CCNE1amp 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 CCNE1amp 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.

Keywords

cell cycle; cyclin-dependent kinase; heterobifunctional degrader; ovarian and breast cancer.

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