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. 2022 Jun 1;23(11):6206. doi: 10.3390/ijms23116206

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© 2022 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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(A) The chemical structure of roscovitine/Seliciclib, CR8, HQ461, and NCT02 as MG compounds; (B) the substrate receptor-independent E3 ligase protein complex model for ubiquitination of the neosubstrate cyclin K. The MG compound CR8 shown in (A) was found through a substrate receptor-independent manner (neither CRBN nor DCAF15 being involved) to glue CDK12–cyclin K directly on DDB1–CUL4 E3 ligase complex to polyubiquitinate cyclin K. Then, the polyubiquitinated cyclin K would be degraded through the ubiquitination proteasome pathway. HQ461 and NCT02 may use a mechanism similar to CR8.