2. Academic Validation
  3. Development and Utility of a PAK1-Selective Degrader

Development and Utility of a PAK1-Selective Degrader

  • J Med Chem. 2022 Dec 8;65(23):15627-15641. doi: 10.1021/acs.jmedchem.2c00756.
Hoi-Yee Chow 1 2,  Sofiia Karchugina 1,  Brian J Groendyke 3,  Sean Toenjes 4,  John Hatcher 3,  Katherine A Donovan 3 5,  Eric S Fischer 3 5,  Gleb Abalakov 1,  Bulat Faezov 1 6,  Roland Dunbrack 1,  Nathanael S Gray 4,  Jonathan Chernoff 1
Affiliations

Affiliations

  • 1 Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States.
  • 2 National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4 Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 6 Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russian Federation.
PMID: 36416208 DOI: 10.1021/acs.jmedchem.2c00756
Abstract

Overexpression of PAK1, a druggable kinase, is common in several malignancies, and inhibition of PAK1 by small molecules has been shown to impede the growth and survival of such cells. Potent inhibitors of PAKs 1-3 have been described, but clinical development has been hindered by recent findings that PAK2 function is required for normal cardiovascular function in adult mice. A unique allosteric PAK1-selective inhibitor, NVS-PAK1-1, provides a potential path forward, but has modest potency. Here, we report the development of BJG-05-039, a PAK1-selective degrader consisting of NVS-PAK1-1 conjugated to lenalidomide, a recruiter of the E3 ubiquitin Ligase substrate adaptor Cereblon. BJG-05-039 induced selective degradation of PAK1 and displayed enhanced anti-proliferative effects relative to its parent compound in PAK1-dependent, but not PAK2-dependent, cell lines. Our findings suggest that selective PAK1 degradation may confer more potent pharmacological effects compared with catalytic inhibition and highlight the potential advantages of PAK1-targeted degradation.

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