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Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization

The marine natural product fascaplysin (1) is a potent Cdk4 (cyclin-dependent kinase 4)-specific inhibitor, but is toxic to all cell types possibly because of its DNA-intercalating properties. Through the design and synthesis of numerous fascaplysin analogues, we intended to identify inhibitors of c...

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Autores principales: Mahale, S, Bharate, S B, Manda, S, Joshi, P, Jenkins, P R, Vishwakarma, R A, Chaudhuri, B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669722/
https://www.ncbi.nlm.nih.gov/pubmed/25950473
http://dx.doi.org/10.1038/cddis.2015.96
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author Mahale, S
Bharate, S B
Manda, S
Joshi, P
Jenkins, P R
Vishwakarma, R A
Chaudhuri, B
author_facet Mahale, S
Bharate, S B
Manda, S
Joshi, P
Jenkins, P R
Vishwakarma, R A
Chaudhuri, B
author_sort Mahale, S
collection PubMed
description The marine natural product fascaplysin (1) is a potent Cdk4 (cyclin-dependent kinase 4)-specific inhibitor, but is toxic to all cell types possibly because of its DNA-intercalating properties. Through the design and synthesis of numerous fascaplysin analogues, we intended to identify inhibitors of cancer cell growth with good therapeutic window with respect to normal cells. Among various non-planar tryptoline analogues prepared, N-(biphenyl-2-yl) tryptoline (BPT, 6) was identified as a potent inhibitor of cancer cell growth and free from DNA-binding properties owing to its non-planar structure. This compound was tested in over 60 protein kinase assays. It displayed inhibition of Cdk4-cyclin D1 enzyme in vitro far more potently than many other kinases including Cdk family members. Although it blocks growth of cancer cells deficient in the mitotic-spindle checkpoint at the G(0)/G(1) phase of the cell cycle, the block occurs primarily at the G(2)/M phase. BPT inhibits tubulin polymerization in vitro and acts as an enhancer of tubulin depolymerization of paclitaxel-stabilized tubulin in live cells. Western blot analyses indicated that, in p53-positive cells, BPT upregulates the expression of p53, p21 and p27 proteins, whereas it downregulates the expression of cyclin B1 and Cdk1. BPT selectively kills SV40-transformed mouse embryonic hepatic cells and human fibroblasts rather than untransformed cells. BPT inhibited the growth of several human cancer cells with an IC(50) <1 μM. The pharmacokinetic study in BALB/c mice indicated good plasma exposure after intravenous administration. It was found to be efficacious at 1/10th the maximum-tolerated dose (1000 mg/kg) against human tumours derived from HCT-116 (colon) and NCI-H460 (lung) cells in SCID (severe-combined immunodeficient) mice models. BPT is a relatively better anticancer agent than fascaplysin with an unusual ability to block two overlapping yet crucial phases of the cell cycle, mitosis and G(0)/G(1). Its ability to effectively halt tumour growth in human tumour-bearing mice would suggest that BPT has the potential to be a candidate for further clinical development.
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spelling pubmed-46697222015-12-04 Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization Mahale, S Bharate, S B Manda, S Joshi, P Jenkins, P R Vishwakarma, R A Chaudhuri, B Cell Death Dis Original Article The marine natural product fascaplysin (1) is a potent Cdk4 (cyclin-dependent kinase 4)-specific inhibitor, but is toxic to all cell types possibly because of its DNA-intercalating properties. Through the design and synthesis of numerous fascaplysin analogues, we intended to identify inhibitors of cancer cell growth with good therapeutic window with respect to normal cells. Among various non-planar tryptoline analogues prepared, N-(biphenyl-2-yl) tryptoline (BPT, 6) was identified as a potent inhibitor of cancer cell growth and free from DNA-binding properties owing to its non-planar structure. This compound was tested in over 60 protein kinase assays. It displayed inhibition of Cdk4-cyclin D1 enzyme in vitro far more potently than many other kinases including Cdk family members. Although it blocks growth of cancer cells deficient in the mitotic-spindle checkpoint at the G(0)/G(1) phase of the cell cycle, the block occurs primarily at the G(2)/M phase. BPT inhibits tubulin polymerization in vitro and acts as an enhancer of tubulin depolymerization of paclitaxel-stabilized tubulin in live cells. Western blot analyses indicated that, in p53-positive cells, BPT upregulates the expression of p53, p21 and p27 proteins, whereas it downregulates the expression of cyclin B1 and Cdk1. BPT selectively kills SV40-transformed mouse embryonic hepatic cells and human fibroblasts rather than untransformed cells. BPT inhibited the growth of several human cancer cells with an IC(50) <1 μM. The pharmacokinetic study in BALB/c mice indicated good plasma exposure after intravenous administration. It was found to be efficacious at 1/10th the maximum-tolerated dose (1000 mg/kg) against human tumours derived from HCT-116 (colon) and NCI-H460 (lung) cells in SCID (severe-combined immunodeficient) mice models. BPT is a relatively better anticancer agent than fascaplysin with an unusual ability to block two overlapping yet crucial phases of the cell cycle, mitosis and G(0)/G(1). Its ability to effectively halt tumour growth in human tumour-bearing mice would suggest that BPT has the potential to be a candidate for further clinical development. Nature Publishing Group 2015-05 2015-05-07 /pmc/articles/PMC4669722/ /pubmed/25950473 http://dx.doi.org/10.1038/cddis.2015.96 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Mahale, S
Bharate, S B
Manda, S
Joshi, P
Jenkins, P R
Vishwakarma, R A
Chaudhuri, B
Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization
title Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization
title_full Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization
title_fullStr Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization
title_full_unstemmed Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization
title_short Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization
title_sort antitumour potential of bpt: a dual inhibitor of cdk4 and tubulin polymerization
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669722/
https://www.ncbi.nlm.nih.gov/pubmed/25950473
http://dx.doi.org/10.1038/cddis.2015.96
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