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.
Yongtao Li  1 ,  Qingxiang Guo  1 ,  Chao Zhang  2 ,  Zhi Huang  2 ,  Tianqi Wang  2 ,  Xin Wang  2 ,  Xiang Wang  2 ,  Guangwei Xu  2 ,  Yanhua Liu  2 ,  Shengyong Yang  3 ,  Yan Fan  4 ,  Rong Xiang  5
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: [email protected].
  • 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: [email protected].
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.
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