2. Academic Validation
  3. Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders

Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders

  • J Med Chem. 2022 Feb 10;65(3):2313-2328. doi: 10.1021/acs.jmedchem.1c01768.
Jibu Lu 1 2,  Yongjun Huang 3,  Jing Huang 3,  Rui He 3,  Minhao Huang 1,  Xiaoyun Lu 3,  Yong Xu 1 4,  Fengtao Zhou 3,  Zhang Zhang 3,  Ke Ding 3 5 6
Affiliations

Affiliations

  • 1 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 2 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 3 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 4 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 5 The First Affiliated Hospital (Huaqiao Hospital), Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 6 State Key Laboratory of Bioorganic Chemistry and Nature Products, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No.345 Lingling Road, 200032 Shanghai, China.
PMID: 35084180 DOI: 10.1021/acs.jmedchem.1c01768
Abstract

The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal Cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders 8e and 8j demonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts 8q and 8r. Degraders 8e and 8j also demonstrated reasonable PK profiles and exhibited potent target degradation and in vivo Anticancer efficacy in a xenograft mouse model of COLO-205 human colorectal Cancer cells upon i.p. administration.

Figures
Products