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

doi:10.1016/j.bmcl.2017.06.041

Bioorganic & Medicinal Chemistry Letters

Volume 27, Issue 15, 1 August 2017, Pages 3231-3237

https://doi.org/10.1016/j.bmcl.2017.06.041 Get rights and content

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 = 12 nM. 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.

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Acknowledgments

This work was supported by the Natural Science Foundation of Tianjin (17JCQNJC13500) and National Key Scientific Research Project (2013CB967201) and the National Natural Science Foundation of China (81470354) and Research Found of the Doctoral Program of Higher Education of China (No. 20100031120044).

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Protein kinases are important drug targets, especially in the area of oncology. This paper reports the synthesis and biological evaluation of new 7-azaindole derivatives bearing benzocycloalkanone motifs as potential protein kinase inhibitors. Four compounds 8g, 8h, 8i, and 8l were discovered to inhibit cyclin-dependent kinase 9 (CDK9/CyclinT) and/or Haspin kinase in the micromolar to nanomolar range. 8l was identified as the most potent Haspin inhibitor (IC₅₀ = 14 nM), while 8g and 8h acted as dual inhibitors of CDK9/CyclinT and Haspin. These novel compounds constitute a promising starting point for the discovery of dual protein kinase inhibitors that have potential to be developed as anticancer agents, since both CDK9/CyclinT and Haspin are considered to be drug targets in oncology.
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^f: Yongtao Li and Qingxiang Guo are contributed equally to this work.

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

Abstract

Graphical abstract

Section snippets

Acknowledgments

Trends Pharmacol Sci

Bioorg Med Chem

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Pharmacol Res

Eur J Med Chem

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Nobel Prize in Physiology or Medicine. Cycling toward Stockholm

Science

CDK9 a potential target for drug development

Med Chem

Spectrum and degree of CDK drug interactions predicts clinical performance

Mol Cancer Ther