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Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

ABSTRACT: Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

PROVIDER: PRJNA292774 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR2157610.fastq.gz	Fastqsanger.gz
	SRR2157611.fastq.gz	Fastqsanger.gz
	SRR2157608.fastq.gz	Fastqsanger.gz
	SRR2157609.fastq.gz	Fastqsanger.gz
	SRR3175540.fastq.gz	Fastqsanger.gz

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Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors [Affymetrix]

Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.

2016-08-29 | GSE72022 | GEO

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors [ChIP-Seq]

2016-05-19 | GSE72023 | GEO

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors.

Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.

| S-EPMC5033074 | biostudies-literature

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-05-19 | GSE72031 | GEO

Covalent targeting of remote cysteine residues for the development of selective CDK12/13 inhibitors

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-08-13 | E-GEOD-72031 | biostudies-arrayexpress

CDK12 and CDK13

Project description:CDK12 and CDK13

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CDK13 cooperates with CDK12 to control global RNA polymerase II processivity

Project description:The RNA polymerase II (POLII) driven transcription cycle is tightly regulated at distinct checkpoints through cyclin dependent kinases (CDKs) and their cognate Cyclins. The molecular events underpinning transcriptional elongation and processivity and CDK-Cyclins involved remain poorly understood. Using CRISPR-CAS9 homology-directed-repair we generated analog-sensitive-kinase variants of CDK12 and CDK13 to probe their individual and shared biological and molecular roles. Single inhibition of CDK12 or CDK13 induced transcriptional responses associated with DNA-damage and cellular growth signaling pathways respectively, with minimal effects on cell viability. In contrast, dual-kinase inhibition potently induced cell death, which was associated with extensive genome-wide transcriptional changes including wide-spread use of alternative 3’ polyadenylation sites. At the molecular level dual-kinase inhibition resulted in the loss of POLII CTD phosphorylation and greatly reduced POLII elongation rates and processivity. These data define significant redundancy between CDK12 and CDK13, and identify both as fundamental regulators of global POLII processivity and transcription elongation.

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