Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate

Yongtao Li; Qingxiang Guo; Chao Zhang; Zhi Huang; Tianqi Wang; Xin Wang; Xiang Wang; Guangwei Xu; Yanhua Liu; Shengyong Yang; Yan Fan; Rong Xiang

doi:10.1016/j.bmcl.2017.06.041

Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3231-3237. doi: 10.1016/j.bmcl.2017.06.041. Epub 2017 Jun 15.

Authors

Yongtao Li¹, Qingxiang Guo¹, Chao Zhang², Zhi Huang², Tianqi Wang², Xin Wang², Xiang Wang², Guangwei Xu², Yanhua Liu², Shengyong Yang³, Yan Fan⁴, Rong Xiang⁵

Affiliations

¹ School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; Tianjin International S & T Cooperation Base, 94 Weijin Road, Tianjin 300071, China.
² School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
³ Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
⁴ School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; International Collaborative Laboratory of Biomedicine of the Ministry of Education, 94 Weijin Road, Tianjin 300071, China. Electronic address: yanfan@nankai.edu.cn.
⁵ School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin 300071, China. Electronic address: rxiang@nankai.edu.cn.

PMID: 28651979
DOI: 10.1016/j.bmcl.2017.06.041

Abstract

A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC₅₀=12nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application.

Keywords: CDK9; Cancer; Inhibitor; LEE011.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminopyridines / chemistry*
Aminopyridines / pharmacology*
Aminopyridines / therapeutic use
Anilides / chemistry
Anilides / pharmacology
Anilides / therapeutic use
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Breast / drug effects
Breast / metabolism
Breast / pathology
Breast Neoplasms / drug therapy
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Cycle / drug effects
Cell Line, Tumor
Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
Cyclin-Dependent Kinase 9 / metabolism
Drug Screening Assays, Antitumor
Female
Humans
Lung / drug effects
Lung / metabolism
Lung / pathology
Lung Neoplasms / drug therapy
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Mice
Mice, Inbred BALB C
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Purines / chemistry*
Purines / pharmacology*
Purines / therapeutic use
Pyridines / chemistry
Pyridines / pharmacology
Pyridines / therapeutic use

Substances

Aminopyridines
Anilides
Antineoplastic Agents
Protein Kinase Inhibitors
Purines
Pyridines
cabozantinib
Cyclin-Dependent Kinase 9
ribociclib