Targeting YAP Degradation by a Novel 1,2,4-Oxadiazole Derivative via Restoration of the Function of the Hippo Pathway

Eman M E Dokla; Chun-Sheng Fang; Po-Chen Chu; Chih-Shiang Chang; Khaled A M Abouzid; Ching S Chen

doi:10.1021/acsmedchemlett.9b00501

Targeting YAP Degradation by a Novel 1,2,4-Oxadiazole Derivative via Restoration of the Function of the Hippo Pathway

ACS Med Chem Lett. 2020 Mar 5;11(4):426-432. doi: 10.1021/acsmedchemlett.9b00501. eCollection 2020 Apr 9.

Authors

Eman M E Dokla¹, Chun-Sheng Fang², Po-Chen Chu³, Chih-Shiang Chang⁴, Khaled A M Abouzid^{1

5}, Ching S Chen^{2

6}

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.
² Institute of New Drug Development, China Medical University, Taichung 40402, Taiwan.
³ Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung 40402, Taiwan.
⁴ School of Pharmacy, College of Pharmacy, China Medical University, Taichung 40402, Taiwan.
⁵ Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City 32897, Egypt.
⁶ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40447, Taiwan.

Abstract

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.