Quantitative Proteomics Reveals Cellular Off-Targets of a DDR1 Inhibitor

Jiaqian Xu; Zhang Zhang; Ligen Lin; Hongyan Sun; Lorenzo V White; Ke Ding; Zhengqiu Li

doi:10.1021/acsmedchemlett.9b00658

Quantitative Proteomics Reveals Cellular Off-Targets of a DDR1 Inhibitor

ACS Med Chem Lett. 2020 Feb 5;11(4):535-540. doi: 10.1021/acsmedchemlett.9b00658. eCollection 2020 Apr 9.

Authors

Jiaqian Xu^{1

2}, Zhang Zhang¹, Ligen Lin³, Hongyan Sun², Lorenzo V White¹, Ke Ding¹, Zhengqiu Li¹

Affiliations

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of China, Guangzhou Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
² Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR 999077, China.
³ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China.

Abstract

Target identification of small molecules is a great challenge but an essential step in drug discovery. Here, a quantitative proteomics approach has been used to characterize the cellular targets of DR, a DDR1 inhibitor. By taking advantage of competitive affinity-based protein profiling coupled with bioimaging, Cathepsin D (CTSD) was found to be the principle off-target of DR in human cancer cells. Further findings suggest the potential of DR as a novel CTSD inhibitor for breast cancer treatment. In addition, a trans-cyclooctene (TCO) containing probe was developed to track the binding between DR and its target proteins in living systems and could be a useful tool for DDR1 detection.