2. Academic Validation
  3. Identification of a new class of activators of the Hippo pathway with antitumor activity in vitro and in vivo

Identification of a new class of activators of the Hippo pathway with antitumor activity in vitro and in vivo

  • Biochem Pharmacol. 2024 Jun:224:116217. doi: 10.1016/j.bcp.2024.116217.
Guifeng Lin 1,  Anjie Xia 2,  Jingxin Qiao 3,  Hailin Zhang 3,  Pei Chen 4,  Pei Zhou 4,  Qian Hu 3,  Zhiyu Xiang 3,  Shiyu Zhang 4,  Linli Li 5,  Shengyong Yang 6
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Fujian Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
  • 2 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 4 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 5 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: lilinli@scu.edu.cn.
  • 6 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yangsy@scu.edu.cn.
PMID: 38641306 DOI: 10.1016/j.bcp.2024.116217
Abstract

The Hippo pathway is a key regulator of tissue growth, organ size, and tumorigenesis. Activating the Hippo pathway by gene editing or pharmaceutical intervention has been proven to be a new therapeutic strategy for treatment of the Hippo pathway-dependent cancers. To now, a number of compounds that directly target the downstream effector proteins of Hippo pathway, including YAP and TEADs, have been disclosed, but very few Hippo pathway activators are reported. Here, we discovered a new class of Hippo pathway activator, YL-602, which inhibited CTGF expression in cells irrespective of cell density and the presence of serum. Mechanistically, YL-602 activates the Hippo pathway via MST1/2, which is different from known activators of Hippo pathway. In vitro, YL-602 significantly induced tumor cell Apoptosis and inhibited colony formation of tumor cells. In vivo, oral administration of YL-602 substantially suppressed the growth of Cancer cells by activation of Hippo pathway. Overall, YL-602 could be a promising lead compound, and deserves further investigation for its mechanism of action and therapeutic applications.

Keywords

Anti-cancer; Drug discovery; Pancreatic cancer; Small molecular activator; Structural optimization; The Hippo pathway.

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