Open AccessTargeting YAP Degradation by a Novel 1,2,4-Oxadiazole Derivative via Restoration of the Function of the Hippo Pathway
Author(s) -
Eman M.E. Dokla,
ChingJu Fang,
Po-Chen Chu,
ChungLiang Chang,
Khaled A. M. Abouzid,
Ching-Shiun Chen
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00501
Subject(s) - hippo signaling pathway , cancer research , kinase , oxadiazole , carcinogenesis , function (biology) , degradation (telecommunications) , chemistry , cancer , microbiology and biotechnology , medicine , biology , biochemistry , computer science , telecommunications , organic chemistry
Recent evidence has linked the dysregulation of the Hippo pathway to tumorigenesis and cancer progression due to its pivotal role in regulating the stability of the oncoprotein YAP. Based on an unexpected finding from the SAR study of a recently reported oxadiazole-based EGFR/c-Met dual inhibitor (compound 1 ), we identified a closely related derivative, compound 2 , which exhibited cogent antitumor activities while devoid of compound 1 's ability to promote EGFR/c-Met degradation. Compound 2 acted, in part, by facilitating YAP degradation through activation of its upstream kinase LATS1. However, it did not alter the phosphorylation status of MST1/2, a LATS1 kinase, suggesting an alternative mechanism for LATS1 activation. Orally administered compound 2 was effective in suppressing MDA-MB-231 xenograft tumor growth while exhibiting a satisfactory safety profile. From a therapeutic perspective, compound 2 might help foster new therapeutic strategies for cancer treatment by restoring the Hippo pathway regulatory function to facilitate YAP degradation.