2. Academic Validation
  3. Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions

Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions

  • J Med Chem. 2023 Apr 10. doi: 10.1021/acs.jmedchem.2c01864.
Yang Gao 1 2,  Baishan Jiang 1 2,  Hellen Kim 1,  Matthew J Berberich 1,  Jianwei Che 1 2,  Katherine A Donovan 2 3,  John M Hatcher 2 3,  Fidel Huerta 1,  Nicholas P Kwiatkowski 1 2 3,  Yingpeng Liu 1 2,  Peter P Liuni 1,  Rebecca J Metivier 1,  Vineeth K Murali 1,  Radosław P Nowak 1 2,  Tinghu Zhang 4,  Eric S Fischer 1 2 3,  Nathanael S Gray 4,  Lyn H Jones 1 2
Affiliations

Affiliations

  • 1 Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, California 94305, United States.
PMID: 37036171 DOI: 10.1021/acs.jmedchem.2c01864
Abstract

Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to Cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in Cancer.

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