Медицинская библиотека · Journal of medicinal chemistry · 2024

Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).

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

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Аннотация

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.

Для цитирования: Gallego Rebecca A, Scales Stephanie, Toledo Chad, Auth Marin, Bernier Louise, Berry Madeline, Brun Sonja, Chung Loanne, Davis Carl, Diehl Wade, Dress Klaus, Eisele Koleen, Elleraas Jeff, Ewanicki Jason, Fobian Yvette, Greasley Samantha, Greenwald Eric C, Johnson Ted W, Khamphavong Penney, Lafontaine Jennifer, Li Jian, Linton Angelica, Maestre Michael, Miller Nichol, Murtaza Anwar, Patman Ryan L, Quinlan Casey L, Ramms Dana J, Richardson Paul, Sach Neal, Salomon-Ferrer Romelia, Silva Francisco, Timofeevski Sergei, Tran Phuong, Tran-Dubé Michelle, Wang Fen, Wang Wei, Wythes Martin, Yang Shouliang, Zou Aihua, VanArsdale Todd, McAlpine Indrawan. Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).. Journal of medicinal chemistry. 2024. DOI: 10.1021/acs.jmedchem.4c01659.

Предметные рубрики MeSH

Humans Protein Serine-Threonine Kinases Structure-Activity Relationship Protein Kinase Inhibitors Cell Line, Tumor Animals Antineoplastic Agents Cell Proliferation Models, Molecular Drug Discovery Mice Drug Design Microtubule-Associated Proteins

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