title: A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors.
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.
authors.affiliation: a Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.|b Tufts University School of Medicine , Boston , MA , USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Eliades
authors.affiliation: a Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.|c Department of Medicine , Brigham and Women's Hospital , Boston , MA , USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Miller
authors.affiliation: a Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
authors.forename: Benchun
authors.initials: B
authors.lastname: Miao
authors.affiliation: a Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
authors.affiliation: a Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Taylor
authors.affiliation: d Piramal Enterprises Limited , Mumbai , India.
authors.forename: Shama
authors.initials: S
authors.lastname: Buch
authors.affiliation: d Piramal Enterprises Limited , Mumbai , India.
authors.forename: Sreesha P
authors.initials: SP
authors.lastname: Srinivasa
authors.affiliation: e Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: a Wellman Center for Photomedicine and Department of Dermatology, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
mesh_terms: D002453:Cell Cycle / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases
keywords: Cell cycle; MAPK pathways; melanoma, multi-CDK inhibitor; synergy
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