Discovery of Novel and Highly Selective Cyclopropane ALK Inhibitors through a Fragment-Assisted, Structure-Based Drug Design.

Autor:	Fujimori I; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Wakabayashi T; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Murakami M; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Okabe A; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., Ishii T; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan., McGrath A; Takeda California, Inc., 10410 Science Center Drive, San Diego, California 92121, United States., Zou H; Takeda California, Inc., 10410 Science Center Drive, San Diego, California 92121, United States., Saikatendu KS; Takeda California, Inc., 10410 Science Center Drive, San Diego, California 92121, United States., Imoto H; Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Jazyk:	angličtina
Zdroj:	ACS omega [ACS Omega] 2020 Nov 30; Vol. 5 (49), pp. 31984-32001. Date of Electronic Publication: 2020 Nov 30 (Print Publication: 2020).
DOI:	10.1021/acsomega.0c04900
Abstrakt:	Fragment screening is frequently used for hit identification. However, there was no report starting from a small fragment for the development of an anaplastic lymphoma kinase (ALK) inhibitor, despite the number of ALK inhibitors reported. We began our research with the fragment hit F-1 and our subsequent linker design, and its docking analysis yielded novel cis -1,2,2-trisubstituted cyclopropane 1 . The fragment information was integrated with a structure-based approach to improve upon the selectivity over tropomyosin receptor kinase A, leading to the potent and highly selective ALK inhibitor, 4-trifluoromethylphenoxy- cis -1,2,2-trisubstituted cyclopropane 12 . This work shows that fragments become a powerful tool for both lead generation and optimization, such as the improvement of selectivity, by combining them with a structure-based drug design approach, resulting in the fast and efficient development of a novel, potent, and highly selective compound. Competing Interests: The authors declare no competing financial interest. (© 2020 American Chemical Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu