A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors. Issue 7 (2nd July 2016)

• Record Type: Journal Article
• Authors: Eliades, Philip; Miller, David M.; Miao, Benchun; Kumar, Raj; Taylor, Michael; Buch, Shama; Srinivasa, Sreesha P.; Flaherty, Keith T.; Tsao, Hensin
• Is Part Of: Cancer biology & therapy. Volume 17:Issue 7(2016)
• Page Start: 778
• Page End: 784
• Publication Date: 2016-07-02
• Subjects: Cell cycle -- MAPK pathways -- melanoma, multi-CDK inhibitor -- synergy; 616.99406
• DOI: 10.1080/15384047.2016.1139267
• Languages: English
• ISSNs: 1538-4047

Abstract

ABSTRACT: 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.