Absence of CDK12 in oocyte leads to female infertility

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Март 27, 2025

Язык: Английский

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Transcriptional cyclin-dependent kinases: Potential drug targets in cancer therapy

European Journal of Medicinal Chemistry, Год журнала: 2021, Номер 229, С. 114056 - 114056

Опубликована: Дек. 16, 2021

Язык: Английский

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Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(20), С. 18247 - 18264

Опубликована: Окт. 10, 2024

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery ZLC491 potent, selective, bioavailable PROTAC degrader. The compound effectively degraded CDK12 CDK13 with DC50 values 32 28 nM, respectively, in TNBC MDA-MB-231 cells. Global proteomic assessment mechanistic studies revealed that selectively induced cereblon- proteasome-dependent manner. Furthermore, molecule efficiently suppressed transcription expression long genes, predominantly subset genes associated DNA damage response, significantly inhibited proliferation multiple cell lines. Importantly, achieved an oral bioavailability 46.8% rats demonstrated potent vivo degradative effects on xenografted mouse model.

Язык: Английский

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Current progress and novel strategies that target CDK12 for drug discovery

European Journal of Medicinal Chemistry, Год журнала: 2022, Номер 240, С. 114603 - 114603

Опубликована: Июль 12, 2022

Язык: Английский

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A practical “preTACs-cytoblot” platform accelerates the streamlined development of PROTAC-based protein degraders

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 251, С. 115248 - 115248

Опубликована: Март 7, 2023

Язык: Английский

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