A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors.

Cancer Biol Ther 2016 07;17(7):778-84

a Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.

Nearly 100% of melanomas have a defect in the p16(INK4A):cyclin D-CDK4/6:RB pathway, leading to abnormal cell cycle control and unregulated cellular proliferation. Here, we report that P1446A-05, a novel multi-CDK inhibitor has significant inhibitory activity against cutaneous and uveal melanoma. Mechanistic studies revealed that P1446A-05 inhibits phosphorylation targets of CDK members, and induces cell cycle arrest and apoptosis irrespective of melanoma genotype or phenotype. Additionally, we show preclinical evidence that P1446A-05 can synergize with other small molecule inhibitors previously studied in melanoma. Collectively, these data demonstrate that targeting cell cycle and transcriptional CDKs with a small molecule multi-CDK inhibitor is a viable approach for developing novel anti-melanoma therapeutics.

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http://dx.doi.org/10.1080/15384047.2016.1139267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970529PMC
July 2016
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References

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Gupta S et al.
J Clin Oncol: Off J Am Soc Clin Oncol. 2012

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