Discovery of Selective and Orally Bioavailable Heterobifunctional Degraders of Cyclin-Dependent Kinase 2
Cyclin-dependent kinase 2 (CDK2) plays an important role in cell cycle regulation and has emerged as a compelling target for the treatment of cancer, largely because of its potential to overcome the resistance associated with CDK4/6 inhibition. Efforts to develop CDK2 inhibitors have historically proven challenging due to undesirable safety profiles associated with inhibiting off-target CDK isoforms. Herein, we describe the structure-guided discovery of a series of orally bioavailable and selective degraders of CDK2. Degrader <b>37</b> demonstrated improved phenotypic selectivity compared to a clinical CDK2 inhibitor, with greater specificity for disease-relevant cyclin E1 (CCNE1)-amplified cancer cells vs nonamplified cohort. The antitumor activity of <b>37</b> in mice bearing CCNE1-amplified HCC1569 tumors correlated with sustained >90% degradation of CDK2 and sustained 90% inhibition of Rb phosphorylation.
Authors
- C Howarth
- Matthew M. Weiss (ORCID: https://orcid.org/0000-0002-2559-2183)
- Kirti Sharma (ORCID: https://orcid.org/0000-0003-3704-1466)
- Lijing Su (ORCID: https://orcid.org/0000-0003-1533-0988)
- Philip N. Collier (ORCID: https://orcid.org/0000-0002-8355-226X)
- Murugappan Sathappa (ORCID: https://orcid.org/0000-0003-2146-1917)
- Susanne B. Breitkopf
- Tong Liang (ORCID: https://orcid.org/0000-0003-2502-5610)
- Melissa C. Ford
- Kunhua Li (ORCID: https://orcid.org/0000-0002-2360-0397)
- Robert J. Aversa (ORCID: https://orcid.org/0000-0002-9873-4381)
- Nicholas Kwiatkowski (ORCID: https://orcid.org/0000-0002-2092-4185)
- Joseph D. Growney
- Atanu Paul (ORCID: https://orcid.org/0000-0002-9967-6005)
- Brad Enerson
- Xiaozhang Zheng (ORCID: https://orcid.org/0000-0002-8403-7374)
- Dapeng Chen (ORCID: https://orcid.org/0000-0001-8109-8879)
- Juliet Williams
- Rupa R. Sawant
- A.K.M. Shamsuddin and Guang-Yu Yang
Institutions
- Woomera Therapeutics (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01160
- Citations
- 4
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 6.07