Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL)
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.
Authors
- Michael Maestre
- Angelica Linton
- Paul Richardson (ORCID: https://orcid.org/0000-0002-3700-8749)
- Sonja N. Brun
- Eric C. Greenwald (ORCID: https://orcid.org/0000-0003-3600-0750)
- Penney Khamphavong
- Louise Bernier
- Phương Thu Trần (ORCID: https://orcid.org/0000-0002-8875-3108)
- Koleen Eisele
- Francisco J. Silva (ORCID: https://orcid.org/0000-0002-6911-6541)
- Rebecca A. Gallego (ORCID: https://orcid.org/0000-0001-7893-9032)
- Madeline Berry
- Ted W. Johnson (ORCID: https://orcid.org/0000-0002-3541-9747)
- S.E. Greasley (ORCID: https://orcid.org/0000-0002-7978-6477)
- Sergei Timofeevski
- Neal W. Sach (ORCID: https://orcid.org/0000-0002-9966-7459)
- Nichol Miller
- Jason Ewanicki
- Todd VanArsdale
- Loanne Chung
- Martin Wythes
- Ryan L. Patman (ORCID: https://orcid.org/0000-0003-2363-8368)
- Dana J. Ramms (ORCID: https://orcid.org/0000-0002-7700-1728)
- Indrawan McAlpine (ORCID: https://orcid.org/0000-0002-4230-4892)
- Jeff Elleraas
- Casey L. Quinlan (ORCID: https://orcid.org/0000-0002-7808-8271)
- Yvette M. Fobian
- Michelle Tran‐Dubé
- Wade Diehl
- Klaus Dress
- Romelia Salomón–Ferrer
- Wei Wang (ORCID: https://orcid.org/0000-0003-2611-8210)
- Jian Li (ORCID: https://orcid.org/0000-0002-7521-8798)
- Fen Wang (ORCID: https://orcid.org/0000-0003-1035-2205)
- Aihua Zou (ORCID: https://orcid.org/0000-0002-7672-828X)
- Marin Auth
- Chad M. Toledo
- Shouliang Yang
- Carl Davis
- Stephanie Scales
- Jennifer Lafontaine
- Anwar Murtaza
Institutions
- Pfizer (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01659
- Citations
- 5
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 1.63