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ABSTRACT: Rational discovery of Cyclin K molecular glue degraders via scalable chemical profiling

PROVIDER: PRJNA599346 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10841829.fastq.gz	Fastqsanger.gz
	SRR10841830.fastq.gz	Fastqsanger.gz
	SRR10841831.fastq.gz	Fastqsanger.gz
	SRR10841832_1.fastq.gz	Fastqsanger.gz
	SRR10841832_2.fastq.gz	Fastqsanger.gz

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Project description:Molecular glues are small molecules that exert their biologic or therapeutic activities by inducing gain-of-function interactions between pairs of proteins. In particular, molecular-glue degraders, which mediate interactions between target proteins and components of the ubiquitin proteasome system to cause targeted protein degradation, hold great promise as a unique modality for therapeutic targeting of proteins that are currently intractable. Here, we report a new molecular glue HQ461 discovered by high-throughput screening of small molecules that inhibited NRF2 activity. Using unbiased loss-of-function and gain-of-function genetic screening followed by biochemical reconstitution, we show that HQ461 acts by promoting interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of CDK12’s interacting protein Cyclin K (CCNK). Degradation of CCNK mediated by HQ461 compromised CDK12 function, leading to reduced phosphorylation of CDK12 substrate, downregulation of DNA damage response genes, and cell death. Structure-activity relationship analysis of HQ461 revealed the importance of a 5-methylthiazol-2-amine pharmacophore and resulted in an HQ461 derivate with improved potency. Our studies reveal a new molecular glue that engages its target protein directly with DDB1 to bypass the requirement of a substrate-specific receptor, presenting a new strategy for targeted protein degradation.

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