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.
Rebecca A Gallego  1 Stephanie Scales  1 Chad Toledo  2 Marin Auth  2 Louise Bernier  1 Madeline Berry  1 Sonja Brun  2 Loanne Chung  1 Carl Davis  2 Wade Diehl  1 Klaus Dress  1 Koleen Eisele  2 Jeff Elleraas  1 Jason Ewanicki  1 Yvette Fobian  1 Samantha Greasley  1 Eric C Greenwald  2 Ted W Johnson  1 Penney Khamphavong  2 Jennifer Lafontaine  1 Jian Li  2 Angelica Linton  1 Michael Maestre  2 Nichol Miller  2 Anwar Murtaza  2 Ryan L Patman  1 Casey L Quinlan  2 Dana J Ramms  2 Paul Richardson  1 Neal Sach  1 Romelia Salomon-Ferrer  1 Francisco Silva  1 Sergei Timofeevski  2 Phuong Tran  1 Michelle Tran-Dubé  1 Fen Wang  1 Wei Wang  1 Martin Wythes  1 Shouliang Yang  1 Aihua Zou  2 Todd VanArsdale  2 Indrawan McAlpine  1
Affiliations
  • 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.
Abstract

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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