| Autor: |
Chow HY; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States.; National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China., Karchugina S; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States., Groendyke BJ; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States., Toenjes S; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., Hatcher J; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States., Donovan KA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States., Fischer ES; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States., Abalakov G; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States., Faezov B; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States.; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russian Federation., Dunbrack R; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States., Gray NS; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., Chernoff J; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States. |
| Abstrakt: |
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. |
