Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL)
- J Med Chem. 2024 Nov 14;67(21):19234-19246. doi: 10.1021/acs.jmedchem.4c01659.
- 1. Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, 10770 Science Center Drive, La Jolla, California 92121, United States.
- 2. Oncology Research Unit, Pfizer Worldwide Research and Development, 10770 Science Center Drive, La Jolla, California 92121, United States.
By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.
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