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ID: ALA4052710
Journal: Bioorg Med Chem Lett
Title: Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate.
Authors: Li Y, Guo Q, Zhang C, Huang Z, Wang T, Wang X, Wang X, Xu G, Liu Y, Yang S, Fan Y, Xiang R.
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.
CiteXplore: 28651979