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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