Cargando…

Investigational cyclin-dependent kinase 4/6 inhibitor GLR2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models

Cyclin-dependent kinases, CDK4 and CDK6, are essential in regulating the cell cycle, which is disrupted in cancers like isocitrate dehydrogenase wild-type glioblastoma (GBM). Currently marketed CDK4/6 inhibitors, including abemaciclib, have shown preclinical efficacy in solid tumors, but factors suc...

Descripción completa

Detalles Bibliográficos
Autores principales: Yin, Lei, Yao, Zhenglin, Wang, Yue, Mazuranic, Michelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9403987/
https://www.ncbi.nlm.nih.gov/pubmed/36033522
http://dx.doi.org/10.3389/fonc.2022.915862
_version_ 1784773505387069440
author Yin, Lei
Yao, Zhenglin
Wang, Yue
Mazuranic, Michelle
author_facet Yin, Lei
Yao, Zhenglin
Wang, Yue
Mazuranic, Michelle
author_sort Yin, Lei
collection PubMed
description Cyclin-dependent kinases, CDK4 and CDK6, are essential in regulating the cell cycle, which is disrupted in cancers like isocitrate dehydrogenase wild-type glioblastoma (GBM). Currently marketed CDK4/6 inhibitors, including abemaciclib, have shown preclinical efficacy in solid tumors, but factors such as poor blood–brain barrier (BBB) penetration limit their efficacy in GBM. GLR2007 is an investigational CDK4/6 inhibitor with the potential for improved BBB penetration. In vitro assays were used to assess the potency and inhibition of CDK4/6 enzymatic activity of GLR2007. Using in vivo assays, the distribution of radiolabeled GLR2007 in rats was determined through quantitative whole-body autoradiography. The antitumor efficacy of GLR2007 was evaluated in human GBM and breast cancer orthotopic mice xenograft models, and human lung, colorectal, and liver cancer in a subcutaneous xenograft model. In tumor cell line proliferation assays, GLR2007 inhibited proliferation at lower concentration values than abemaciclib in 19 of 20 GBM, five of seven breast, 20 of 21 lung, and 24 of 24 liver cancer cell lines. Total levels of radiolabeled GLR2007 in the brains of rats exceeded those in plasma by 2.3–4.5-fold from 2–6 hours after dosing. A xenograft model showed that, compared with vehicle control, 50 mg/kg GLR2007 induced 95.9% tumor growth inhibition (TGI) (P<0.001) in GBM orthotopic xenografts, 81.4% TGI (P=0.037) in breast cancer orthotopic xenografts, and 91.5% TGI (P<0.001) in colorectal cancer subcutaneous xenografts. These studies show possible BBB penetration of GLR2007 and demonstrate its potential as a CDK4/6 inhibitor for the treatment of solid tumors, including GBM.
format Online
Article
Text
id pubmed-9403987
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-94039872022-08-26 Investigational cyclin-dependent kinase 4/6 inhibitor GLR2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models Yin, Lei Yao, Zhenglin Wang, Yue Mazuranic, Michelle Front Oncol Oncology Cyclin-dependent kinases, CDK4 and CDK6, are essential in regulating the cell cycle, which is disrupted in cancers like isocitrate dehydrogenase wild-type glioblastoma (GBM). Currently marketed CDK4/6 inhibitors, including abemaciclib, have shown preclinical efficacy in solid tumors, but factors such as poor blood–brain barrier (BBB) penetration limit their efficacy in GBM. GLR2007 is an investigational CDK4/6 inhibitor with the potential for improved BBB penetration. In vitro assays were used to assess the potency and inhibition of CDK4/6 enzymatic activity of GLR2007. Using in vivo assays, the distribution of radiolabeled GLR2007 in rats was determined through quantitative whole-body autoradiography. The antitumor efficacy of GLR2007 was evaluated in human GBM and breast cancer orthotopic mice xenograft models, and human lung, colorectal, and liver cancer in a subcutaneous xenograft model. In tumor cell line proliferation assays, GLR2007 inhibited proliferation at lower concentration values than abemaciclib in 19 of 20 GBM, five of seven breast, 20 of 21 lung, and 24 of 24 liver cancer cell lines. Total levels of radiolabeled GLR2007 in the brains of rats exceeded those in plasma by 2.3–4.5-fold from 2–6 hours after dosing. A xenograft model showed that, compared with vehicle control, 50 mg/kg GLR2007 induced 95.9% tumor growth inhibition (TGI) (P<0.001) in GBM orthotopic xenografts, 81.4% TGI (P=0.037) in breast cancer orthotopic xenografts, and 91.5% TGI (P<0.001) in colorectal cancer subcutaneous xenografts. These studies show possible BBB penetration of GLR2007 and demonstrate its potential as a CDK4/6 inhibitor for the treatment of solid tumors, including GBM. Frontiers Media S.A. 2022-08-11 /pmc/articles/PMC9403987/ /pubmed/36033522 http://dx.doi.org/10.3389/fonc.2022.915862 Text en Copyright © 2022 Yin, Yao, Wang and Mazuranic https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Yin, Lei
Yao, Zhenglin
Wang, Yue
Mazuranic, Michelle
Investigational cyclin-dependent kinase 4/6 inhibitor GLR2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models
title Investigational cyclin-dependent kinase 4/6 inhibitor GLR2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models
title_full Investigational cyclin-dependent kinase 4/6 inhibitor GLR2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models
title_fullStr Investigational cyclin-dependent kinase 4/6 inhibitor GLR2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models
title_full_unstemmed Investigational cyclin-dependent kinase 4/6 inhibitor GLR2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models
title_short Investigational cyclin-dependent kinase 4/6 inhibitor GLR2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models
title_sort investigational cyclin-dependent kinase 4/6 inhibitor glr2007 demonstrates activity against isocitrate dehydrogenase wild-type glioblastoma and other solid tumors in mice xenograft models
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9403987/
https://www.ncbi.nlm.nih.gov/pubmed/36033522
http://dx.doi.org/10.3389/fonc.2022.915862
work_keys_str_mv AT yinlei investigationalcyclindependentkinase46inhibitorglr2007demonstratesactivityagainstisocitratedehydrogenasewildtypeglioblastomaandothersolidtumorsinmicexenograftmodels
AT yaozhenglin investigationalcyclindependentkinase46inhibitorglr2007demonstratesactivityagainstisocitratedehydrogenasewildtypeglioblastomaandothersolidtumorsinmicexenograftmodels
AT wangyue investigationalcyclindependentkinase46inhibitorglr2007demonstratesactivityagainstisocitratedehydrogenasewildtypeglioblastomaandothersolidtumorsinmicexenograftmodels
AT mazuranicmichelle investigationalcyclindependentkinase46inhibitorglr2007demonstratesactivityagainstisocitratedehydrogenasewildtypeglioblastomaandothersolidtumorsinmicexenograftmodels