Discovery of a small-molecule inhibitor of carbamoyl phosphate synthase 1 and its anti-colorectal cancer mechanism
10.16438/j.0513-4870.2022-0385
- VernacularTitle:CPS1小分子抑制剂的筛选及其抗结直肠癌的机制研究
- Author:
Xing JIANG
1
;
Wen-ke JIN
1
;
Zi-xiang LI
1
;
Bo LIU
2
;
Lei-lei FU
1
Author Information
1. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
2. State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu 610041, China
- Publication Type:Research Article
- Keywords:
carbamoyl phosphate synthase 1;
colorectal cancer;
high-throughput virtual screening;
small-molecule inhibitor;
cell cycle arrest;
apoptosis
- From:
Acta Pharmaceutica Sinica
2022;57(9):2671-2681
- CountryChina
- Language:Chinese
-
Abstract:
The carbamoyl phosphate synthase 1 (CPS1) enzyme is involved in the first phase of the urea cycle, providing a prerequisite molecule for pyrimidine synthesis, as well as promoting tumor cell proliferation and growth. Studies have found that CPS1 is highly expressed in a variety of tumors, including colorectal cancer, lung cancer, etc. and its overexpression is related to the poor prognosis of tumors. Thus, small molecules targeted to inhibit the function of CPS1 in tumors may provide therapeutic benefits for cancer patients who overexpress CPS1. In this study, the function of CPS1 was investigated in vitro, and we found that overexpression of CPS1 can enhance the migration ability of colorectal cancer cells HCT15. Here, based upon the existing crystal structure, combined with high-throughput virtual screening, we obtained 8 candidate small molecule compounds. In vitro activity evaluation, we found that compound 3 has good anti-HCT15, HCT116 cell proliferation activity (HCT15, IC50, 7.69 ± 1.10 μmol‧L-1, HCT116, IC50, 13.53 ± 0.46 μmol‧L-1). Subsequently, molecular docking and molecular dynamics (MD) simulation analysis showed that, compound 3 could target and inhibit the activity of CPS1. In vitro studies showed that compound 3 could inhibit the migration of HCT15 cells, as well as induced cell cycle arrest and apoptosis. Taken together, this study found that compound 3 is a potential small molecule inhibitor that targets CPS1, which provides the experimental basis and theoretical basis for the development of targeted intervention small molecule therapeutic drugs. Based upon the chemical structure of compound 3, we will shed new light on further optimizing its activity and therapeutic potential, which may provide a therapeutic benefit to the patients with CPS1-related tumors.
