Discovery of a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors

Chen Shi; Qian Wang; Xuemei Liao; Hui Ge; Guoyong Huo; Leduo Zhang; Na Chen; Xiong Zhai; Yuan Hong; Li Wang; Zhe Wang; Weijun Shi; Yu Mao; Jianxin Yu; Ying Ke; Guangxin Xia

doi:10.1016/j.ejmech.2020.112239

Discovery of a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors

Eur J Med Chem. 2020 May 1:193:112239. doi: 10.1016/j.ejmech.2020.112239. Epub 2020 Mar 16.

Authors

Chen Shi¹, Qian Wang¹, Xuemei Liao¹, Hui Ge¹, Guoyong Huo¹, Leduo Zhang¹, Na Chen¹, Xiong Zhai¹, Yuan Hong¹, Li Wang¹, Zhe Wang¹, Weijun Shi¹, Yu Mao¹, Jianxin Yu¹, Ying Ke², Guangxin Xia³

Affiliations

¹ Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China.
² Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China. Electronic address: key@sphchina.com.
³ Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China. Electronic address: xiagx@sphchina.com.

PMID: 32200202
DOI: 10.1016/j.ejmech.2020.112239

Abstract

CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.

Keywords: Antitumor; CDK4/6 inhibitors; Cell cycle.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Male
Mice
Mice, Inbred BALB C
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tissue Distribution

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6