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Targeting YAP Degradation by a Novel 1,2,4-Oxadiazole Derivative via Restoration of the Function of the Hippo Pathway.
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2020-03-05 , DOI: 10.1021/acsmedchemlett.9b00501
Eman M E Dokla,Chun-Sheng Fang,Po-Chen Chu,Chih-Shiang Chang,Khaled A M Abouzid,Ching S Chen

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.

中文翻译:

通过恢复河马通路的功能,通过新型1,2,4-恶二唑衍生物靶向YAP降解。

由于其在调节癌蛋白YAP稳定性中的关键作用,最近的证据已将河马途径的失调与肿瘤发生和癌症进展联系起来。基于最近报道的基于恶二唑的EGFR / c-Met双重抑制剂(化合物1)的SAR研究的意外发现,我们确定了一种密切相关的衍生物化合物2,该化合物表现出有效的抗肿瘤活性,而没有化合物1的能力促进EGFR / c-Met降解。化合物2的部分作用是通过激活其上游激酶LATS1来促进YAP降解。但是,它没有改变LATS1激酶MST1 / 2的磷酸化状态,提示LATS1激活的另一种机制。口服给药的化合物2在抑制MDA-MB-231异种移植肿瘤生长方面是有效的,同时表现出令人满意的安全性。从治疗的角度来看,化合物2通过恢复Hippo通路的调节功能以促进YAP降解,可能有助于促进癌症治疗的新治疗策略。
更新日期:2020-04-23
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