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Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition [bulk]

ABSTRACT: Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition [bulk]

PROVIDER: PRJNA1090423 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28408545_1.fastq.gz	Fastqsanger.gz
	SRR28408545_2.fastq.gz	Fastqsanger.gz
	SRR28408546_1.fastq.gz	Fastqsanger.gz
	SRR28408546_2.fastq.gz	Fastqsanger.gz
	SRR28408547_1.fastq.gz	Fastqsanger.gz

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Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition [nascent]

Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Aberrant CDK12 expression, homozygous loss, and mutations have been documented in various malignancies. Previous studies have demonstrated CDK12 and 13 are promising therapeutic targets in cancer. In this study, we developed a selective CDK12/13 PROTAC degrader YJ9069, which in a panel of cancer cell lines, affirm its effectiveness in inhibiting cell proliferation in subsets of cancer. CDK12/13 degradation rapidly triggers gene-length dependent transcriptional elongation defects, leading to DNA damage and cell cycle arrest. In vivo, YJ9069 significantly suppresses tumor growth in prostate cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Modifications of YJ9069 yielded a first-in-class orally bioavailable CDK12/13 degrader, YJ1206, which exhibits a comparable efficacy with significantly less toxicity. To identify pathways that may be synthetically lethal upon CDK12/13 degradation, we screened phosphorylation pathway arrays employing cell lines treated with YJ1206. Interestingly, degradation or genetic knock-down of CDK12/13, led to activation of the Akt pathway. Degradation of CDK12/13 with YJ1206, combined with AKT pathway inhibition with uprosertib, led to a striking synthetic lethal effect in pre-clinical models of prostate cancer. Taken together, these studies demonstrate that combination CDK12/13 and AKT pathway antagonism induces drug-drug synthetic lethality.

2024-08-14 | GSE262120 | GEO

Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition [bulk]

2024-08-14 | GSE262119 | GEO

Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition [nascent]

Project description:Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition [nascent]

| PRJNA1090422 | ENA

Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [WES]

Project description:SWI/SNF ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here we developed AU-24118, a first-in-class, orally bioavailable degrader of SMARCA2/4 and PBRM1. AU-24118 demonstrated tumor regression in a castration resistant model of prostate cancer which was further enhanced in combination with enzalutamide. Prostate cancer cell lines exposed to increasing doses of a SWI/SNF degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. While SMARCA4 mutations provided specific resistance to SWI/SNF degraders, ABCB1 overexpression provided broader resistance to other compounds as well as could be overcome with ABCB1 inhibition.

2024-03-15 | GSE250327 | GEO

Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [RNA-seq]

2024-03-15 | GSE250326 | GEO

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Project description:Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit the target and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. The oral route of administration is the option of choice in the clinic, but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4 deficient cancers. Here we outline structure- and property-guided approaches that led to the first orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.

2022-06-20 | PXD032239 | Pride

Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance

Project description:Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance

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Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition.

Project description:Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells. CDK12/13 degradation rapidly triggers gene-length-dependent transcriptional elongation defects, leading to DNA damage and cell-cycle arrest. In vivo, YJ9069 significantly suppresses prostate tumor growth. Modifications of YJ9069 yielded an orally bioavailable CDK12/13 degrader, YJ1206, which exhibits comparable efficacy with significantly less toxicity. To identify pathways synthetically lethal upon CDK12/13 degradation, phosphorylation pathway arrays were performed using cell lines treated with YJ1206. Interestingly, degradation or genetic knockdown of CDK12/13 led to activation of the AKT pathway. Targeting CDK12/13 for degradation, in conjunction with inhibiting the AKT pathway, resulted in a synthetic lethal effect in preclinical prostate cancer models.

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Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [RNA-seq]

Project description:Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [RNA-seq]

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Blockade of MYCN-dependent transcription using orally-bioavailable CDK9 inhibitors

Project description:Blockade of MYCN-dependent transcription using orally-bioavailable CDK9 inhibitors

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