A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors
Year: 2016
Type: article
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.
Source: Cancer Biology & Therapy
Authors: Philip Eliades, David M. Miller, Benchun Miao, Raj Kumar, Michael Taylor, Shama Buch, Sreesha P. Srinivasa, Keith T. Flaherty, Hensin Tsao
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2267298967