In:
Frontiers in Pharmacology, Frontiers Media SA, Vol. 13 ( 2022-4-11)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1663-9812
DOI:
10.3389/fphar.2022.853993
DOI:
10.3389/fphar.2022.853993.s001
DOI:
10.3389/fphar.2022.853993.s002
DOI:
10.3389/fphar.2022.853993.s003
DOI:
10.3389/fphar.2022.853993.s004
DOI:
10.3389/fphar.2022.853993.s005
DOI:
10.3389/fphar.2022.853993.s006
DOI:
10.3389/fphar.2022.853993.s007
DOI:
10.3389/fphar.2022.853993.s008
DOI:
10.3389/fphar.2022.853993.s009
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2022
detail.hit.zdb_id:
2587355-6
SSG:
15,3
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