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. 2021 May 24;12(6):955-960.
doi: 10.1021/acsmedchemlett.1c00094. eCollection 2021 Jun 10.

Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors

Qing Tang  1 , Alex M Aronov  1 , David D Deininger  1 , Simon Giroux  1 , David J Lauffer  1 , Pan Li  1 , Jianglin Liang  1 , Kira McGinty  1 , Steven Ronkin  1 , Rebecca Swett  1 , Nathan Waal  1 , Diane Boucher  1 , Pamella J Ford  1 , Cameron S Moody  1
Affiliations

Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors

Qing Tang et al. ACS Med Chem Lett. .

Abstract

Herein, we report a novel series of highly potent and selective triazolothiadiazole c-Met inhibitors. Starting with molecule 5, we have applied structure-based drug design principles to identify the triazolothiadiazole ring system. We successfully replaced the metabolically unstable phenolic moiety with a quinoline group. Further optimization around the 5,6 bicyclic moiety led to the identification of 21. Compound 21 suffered from PDE3 selectivity issues and subsequent, structurally informed design led to the discovery of compound 23. Compound 23 has exquisite kinase selectivity, excellent potency, favorable ADME profile, and showed dose-dependent antitumor efficacy in a SNU-5 gastric cancer xenograft model.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Type I and type II c-Met inhibitors.,,
Figure 2
Figure 2
Compound binding modes in the c-Met ATP site pocket and key interactions. (A) Crystal structure of 10 (green). (B) Overlay of quinoline compound 17 (purple) and phenol compound 11 (green). (C) Crystal structures of compound 20 (purple) and 21 (green) superimposed.
Figure 3
Figure 3
Overlay of 21 (A) and 23 (B) with the published MerckI PDE3 inhibitor (green).
Figure 4
Figure 4
In vivo efficacy of 23 in the ectopic human SNU-5 gastric cancer xenograft model in SCID mice. (A) Tumor growth curve; (B) % change in body weight.
See this image and copyright information in PMC

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