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Front Cover: Development and Characterization of Selective FAK Inhibitors and PROTACs with In Vivo Activity (ChemBioChem 19/2023) |
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| Authors: | Eriko Koide Mikaela L Mohardt Zainab M Doctor Annan Yang Mingfeng Hao Katherine A Donovan Christina C Kuismi Alissa J Nelson Kathryn Abell Mike Aguiar Jianwei Che Matthew P Stokes Tinghu Zhang Andrew J Aguirre Eric S Fischer Nathanael S Gray Baishan Jiang Behnam Nabet |
| Affiliation: | 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 USA;2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 USA
These authors contributed equally to this work.;3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 USA;4. Harvard Medical School, Boston, MA 02115 USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 USA;5. Human Biology Division Fred, Hutchinson Cancer Center, Seattle, WA 98109 USA;6. Cell Signaling Technology, Danvers, MA 01923 USA;7. Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford Medicine, Stanford University, Stanford, CA 94305 USA;8. Harvard Medical School, Boston, MA 02115 USA Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215 USA Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02141 USA |
| 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 degraders focal adhesion kinase inhibitors PROTAC |