2. Academic Validation
  3. Development and characterization of selective FAK inhibitors and PROTACs with in vivo activity

Development and characterization of selective FAK inhibitors and PROTACs with in vivo activity

  • Chembiochem. 2023 Apr 23;e202300141. doi: 10.1002/cbic.202300141.
Eriko Koide 1,  Mikaela L Mohardt 1,  Zainab M Doctor 1,  Annan Yang 2,  Mingfeng Hao 1,  Katherine A Donovan 1,  Christina C Kuismi 3,  Alissa J Nelson 4,  Kathryn Abell 4,  Mike Aguiar 4,  Jianwei Che 1,  Matthew P Stokes 4,  Tinghu Zhang 5,  Andrew J Aguirre 6,  Eric S Fischer 1,  Nathanael S Gray 5,  Baishan Jiang 1,  Behnam Nabet 7
Affiliations

Affiliations

  • 1 Dana-Farber Cancer Institute, Department of Cancer Biology, UNITED STATES.
  • 2 Dana-Farber Cancer Institute, Department of Medical Oncology, UNITED STATES.
  • 3 Fred Hutchinson Cancer Center, Human Biology Division, UNITED STATES.
  • 4 Cell Signaling Technology Inc, N/A, UNITED STATES.
  • 5 Stanford University, Department of Chemical and Systems Biology, UNITED STATES.
  • 6 Dana-Farber Cancer Institute, Department of Medical Oncolog, UNITED STATES.
  • 7 Fred Hutchinson Cancer Center, Human Biology Division, 1100 Fairview Ave. N., Mail Stop C1-015, 98109, Seattle, UNITED STATES.
PMID: 37088717 DOI: 10.1002/cbic.202300141
Abstract

Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in Cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK Inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in Cancer Models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in Cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and Cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small molecule inhibition or degradation.

Keywords

Cancer; Degrader; Focal Adhesion Kinase; PROTAC; inhibitor.

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