Evaluation of anti-liver cancer activity and anticancer mechanism of one novel small molecule compound (THY-10A62) targeting FAK pathway

Wanqiu Huang¹Rong Zou¹Jie Xu¹Yuliang Deng¹Dongping Zhang²Yiguo Hu^3*Qian Zhang^2*Jian Huang^1*Zhaoqi Zhang^1,4*

• ¹Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
• ²Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, Shanghai Municipality, China
• ³and Collaborative Innovation Center for Biotherapy, Department of Thyroid Surgery and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
• ⁴Department of Breast and Thyroid Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

The focal adhesion kinase (FAK) is considered as a promising target for the development of novel anticancer drugs. Aberrant overexpression of FAK has been linked to the growth and metastasis of various cancers, including hepatocellular carcinoma (HCC). This research aimed to investigate the antitumor effects of THY-10A62, a novel FAK inhibitor, by employing in vivo models of HCC. In this study, we conducted a preliminary evaluation to assess the therapeutic potential and underlying mechanisms of THY-10A62 against HCC. The maximum tolerated dose (MTD) and median lethal dose (LD50) of THY-10A62 were determined in vivo by evaluating the survival and tolerability of ICR mice following dose escalation experiments. HCC-LM3 cell line-derived xenograft (CDX) model and patient-derived xenograft (PDX) models of liver cancer were employed to analyze the antitumor efficacy of THY-10A62. Protein phosphorylation chip coupled with network pharmacology analyses were employed for the signaling pathway associated with THY-10A62. The MTD of THY-10A62 in mice was below 45 mg/kg. The LD50 for female mice were 49 mg/kg. At a dosage of 15 mg/kg, THY-10A62 treatment exhibited a significant inhibition of liver cancer growth (TGI% > 40%) then PF-562271. THY-10A62 can also significantly down-regulate the FAK phosphorylation level in PDXderived tumors. In addition, THY-10A62 treatment altered the phosphorylation states of BRAF and RASGRF1 proteins downstream effectors of FAK. Our findings provide the evidence that THY-10A62 is a potential and promising FAK inhibitor which can reduce HCC growth in vivo and provide a direction for the development of novel therapeutics for clinical liver cancer treatment in the future.