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

Eliades, Philip; Miller, David M.; Miao, Benchun; Kumar, Raj; Taylor, Michael; Buch, Shama; Srinivasa, Sreesha P.; Flaherty, Keith T.

doi:10.1080/15384047.2016.1139267

Cited by 8 publications

(5 citation statements)

References 26 publications

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“…Voruciclib, a CDK4/6 inhibitor, has shown promising anti-cancer effects in combination with the BRAF inhibitor, vemurafenib in advanced BRAF-mutant melanoma [17]. More recent studies have shown that voruciclib enhances the sensitivity of the proteasome inhibitor, bortezomib, in triple negative breast cancer xenografts [18]. However, there is no published data indicating the sensitizing effects of voruciclib in cells overexpressing ABC transporters.…”

Section: Introductionmentioning

confidence: 99%

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Gupta

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Gupta

Zhang

et al. 2018

Cell Physiol Biochem

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“…It displays potent antiproliferative activity across 30 cancer cell lines, including prostate, colon, and lung cancer cells 215 . It displays synergistic activity with dabrafenib and trametinib in A375 and K4 cell lines 213 . In two phase I studies in patients with advanced refractory tumors, it has shown acceptable safety profile 217,218 .…”

Section: Cdk Inhibitors In Clinical and Preclinical Pipelinementioning

confidence: 99%

“…Voruciclib (P1446A-05, 73) is a structural analog of P276-00 that inhibits CDK9 (IC 50 = 22 nM) and is orally bioavailable. [213][214][215][216] It displays potent antiproliferative activity across 30 cancer cell lines, including prostate, colon, and lung cancer cells. 215 It displays synergistic activity with dabrafenib and trametinib in A375 and K4 cell lines.…”

Section: Aminopyridinesmentioning

confidence: 99%

“…215 It displays synergistic activity with dabrafenib and trametinib in A375 and K4 cell lines. 213 In two phase I studies in patients with advanced refractory tumors, it has shown acceptable safety profile. 217,218 Currently it is being studied in a phase I clinical trial in AML by MEI pharma.…”

Section: Aminopyridinesmentioning

confidence: 99%

“…It was studied in 10 other clinical trials; however, it is currently not under active development. Voruciclib (P1446A‐05, 73 ) is a structural analog of P276‐00 that inhibits CDK9 (IC 50 = 22 nM) and is orally bioavailable 213–216 . It displays potent antiproliferative activity across 30 cancer cell lines, including prostate, colon, and lung cancer cells 215 .…”

Section: Cdk Inhibitors In Clinical and Preclinical Pipelinementioning

confidence: 99%

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Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

Bhurta

Bharate

2021

Medicinal Research Reviews

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Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin‐dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino‐pyrimidine is a well‐represented scaffold. The three‐nitrogen framework of amino‐pyrimidine is a fundamental hinge‐binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose‐limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP‐binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.

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Exploring the potential of chromone scaffold compounds in cancer therapy: targeting key kinase pathways

et al. 2023

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

Cited by 8 publications

References 26 publications

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

Exploring the potential of chromone scaffold compounds in cancer therapy: targeting key kinase pathways

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