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LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer

Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utiliz...

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Autores principales: Qiu, Jiahao, Bai, Xinfa, Zhang, Wenjing, Ma, Mingxu, Wang, Wenyan, Liang, Ye, Wang, Hongbo, Tian, Jingwei, Yu, Pengfei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037595/
https://www.ncbi.nlm.nih.gov/pubmed/35479314
http://dx.doi.org/10.3389/fphar.2022.853993
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author Qiu, Jiahao
Bai, Xinfa
Zhang, Wenjing
Ma, Mingxu
Wang, Wenyan
Liang, Ye
Wang, Hongbo
Tian, Jingwei
Yu, Pengfei
author_facet Qiu, Jiahao
Bai, Xinfa
Zhang, Wenjing
Ma, Mingxu
Wang, Wenyan
Liang, Ye
Wang, Hongbo
Tian, Jingwei
Yu, Pengfei
author_sort Qiu, Jiahao
collection PubMed
description Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthesize three compounds and evaluated their in vitro cytotoxicity. LPM3770277 stood out as the most promising compound which was further confirmed by a series of binding and CDK4/6 degradation studies. LPM3770277 was able to bind to CDK4/6, and time-dependently and dose-dependently increased CDK4/6 protein degradation. Mechanistic study revealed that LPM3770277 exerted its CDK4/6 degradation effect via two machineries: proteasome and lysosome-promoted autophagy. Using in vivo TNBC xenograft cancer model, we found that LPM3770277 demonstrated superior anti-tumor efficacy and safety as compared to abemaciclib, although both compounds exerted similar effects on cell cycle arrest. In conclusion, this study for the first time developed and characterized a CDK4/6 degrader against TNBC using hydrophobic tags, which strongly suggests the viability of hydrophobic tags as a strategy to develop potential treatments against TNBC.
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spelling pubmed-90375952022-04-26 LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer Qiu, Jiahao Bai, Xinfa Zhang, Wenjing Ma, Mingxu Wang, Wenyan Liang, Ye Wang, Hongbo Tian, Jingwei Yu, Pengfei Front Pharmacol Pharmacology Triple negative breast cancer (TNBC) is a subtype of breast cancer with significant malignancy and poor prognosis but effective treatments are limited. Given the critical role of CDK4/6 in cell cycle and the apparent success of CDK4/6 inhibitors against certain cancer, this study attempted to utilize hydrophobic tagging technology to develop a CDK4/6 degrader against TNBC. We based on the chemical structure of the major metabolite of a clinically approved CDK4/6 inhibitor, abemaciclib, to synthesize three compounds and evaluated their in vitro cytotoxicity. LPM3770277 stood out as the most promising compound which was further confirmed by a series of binding and CDK4/6 degradation studies. LPM3770277 was able to bind to CDK4/6, and time-dependently and dose-dependently increased CDK4/6 protein degradation. Mechanistic study revealed that LPM3770277 exerted its CDK4/6 degradation effect via two machineries: proteasome and lysosome-promoted autophagy. Using in vivo TNBC xenograft cancer model, we found that LPM3770277 demonstrated superior anti-tumor efficacy and safety as compared to abemaciclib, although both compounds exerted similar effects on cell cycle arrest. In conclusion, this study for the first time developed and characterized a CDK4/6 degrader against TNBC using hydrophobic tags, which strongly suggests the viability of hydrophobic tags as a strategy to develop potential treatments against TNBC. Frontiers Media S.A. 2022-04-11 /pmc/articles/PMC9037595/ /pubmed/35479314 http://dx.doi.org/10.3389/fphar.2022.853993 Text en Copyright © 2022 Qiu, Bai, Zhang, Ma, Wang, Liang, Wang, Tian and Yu. 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 Pharmacology
Qiu, Jiahao
Bai, Xinfa
Zhang, Wenjing
Ma, Mingxu
Wang, Wenyan
Liang, Ye
Wang, Hongbo
Tian, Jingwei
Yu, Pengfei
LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer
title LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer
title_full LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer
title_fullStr LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer
title_full_unstemmed LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer
title_short LPM3770277, a Potent Novel CDK4/6 Degrader, Exerts Antitumor Effect Against Triple-Negative Breast Cancer
title_sort lpm3770277, a potent novel cdk4/6 degrader, exerts antitumor effect against triple-negative breast cancer
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037595/
https://www.ncbi.nlm.nih.gov/pubmed/35479314
http://dx.doi.org/10.3389/fphar.2022.853993
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