发现微管相关丝氨酸/苏氨酸激酶样 (MASTL) 的高选择性抑制剂

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-11-05 DOI:10.1021/acs.jmedchem.4c0165910.1021/acs.jmedchem.4c01659

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

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引用次数: 0

摘要

由于微管相关丝氨酸/苏氨酸激酶样（MASTL）在细胞增殖中的作用，它是一个新靶点，也是为肿瘤患者提供有影响力的新治疗药物的一流（FIC）机会。在本文中，我们介绍了一项 "命中到先导 "的优化工作，该工作的成果是提供了两种高选择性的 MASTL 抑制剂。实现这项工作的关键策略包括基于结构的药物设计（SBDD）、亲脂效率分析（LipE）和新型合成。由此产生的先进先导化合物促成了一项肿瘤生长抑制研究，该研究对于评估 MASTL 作为肿瘤治疗靶点的潜在价值至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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

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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.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.