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Pharmacological blockade of MYCN in neuroblastoma using orally-bioavailable CDK inhibitors reveals an approach widely applicable to Myc-dependent cancers

ABSTRACT: Pharmacological blockade of MYCN in neuroblastoma using orally-bioavailable CDK inhibitors reveals an approach widely applicable to Myc-dependent cancers

PROVIDER: PRJNA419129 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6308270.fastq.gz	Fastqsanger.gz
	SRR6308271.fastq.gz	Fastqsanger.gz
	SRR6308272.fastq.gz	Fastqsanger.gz
	SRR6308273.fastq.gz	Fastqsanger.gz
	SRR6308268.fastq.gz	Fastqsanger.gz

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Pharmacological blockade of MYCN in neuroblastoma using orally-bioavailable CDK inhibitors reveals an approach widely applicable to Myc-dependent cancers

Project description:Neuroblastoma (NB) is a paediatric tumor wherein amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN confers clinical and biologic features prototypical of Myc-dependent cancers. TF-dependent cancers like MYCN-amplified NB are difficult to target, but the availability of clinical-candidate transcription inhibitors makes selective blockade of oncogenic TF activity a possibility. Here we investigated whether NB could be controlled via dual targeting of the transcription elongation machinery and cell cycle progression, using an orally bioavailable and selective CDK9/2 inhibitor CYC065. CYC065 blocks nascent transcription and leads to a drastic reduction in steady-state levels of short-lived transcripts. In MYCN-amplified NB, CYC065 rapidly and completely eliminated MYCN mRNA and protein, terminating expression of a MYCN-dependent gene expression programme. This result is phenocopied by multiple clinical-candidate CDK9 chemical inhibitors and genetic manipulation of CDK9. Mechanistically, CYC065 dissociates MYCN from physical proximity of P-TEFb in cells. P-TEFb co-occupies promoters and enhancers of de-differentiating pathway genes highly-occupied by MYCN, and CDK9 inhibition terminates expression of these and other highly transcribed genes. Intriguingly, targeted inhibition of CDK9 alone is insufficient to eradicate MYCN-dependent cells lines as CDK9 loss alone is compensated by upregulation of CDK2. CYC065 targeted MYCN-driven neuroblastoma in vivo, resulted in tumor regression or eradication and prolonged survival in multiple NB models, and was effective against a wide range of Myc-dependent cancer cells lines in vitro. The data establish that combined CDK9/CDK2 inhibition blocks transcriptional dependence induced by MYCN, highlighting a potential clinical strategy by which many Myc-driven cancers could be targeted.

2019-01-01 | GSE107126 | 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

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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Pharmacological blockade of high-risk MYCN driven neuroblastoma using an orally-bioavailable CDK2/9 inhibitor

Project description:Pharmacological blockade of high-risk MYCN driven neuroblastoma using an orally-bioavailable CDK2/9 inhibitor

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Pharmacological blockade of high-risk MYCN driven neuroblastoma using an orally-bioavailable CDK2/9 inhibitor

Project description:Pharmacological blockade of high-risk MYCN driven neuroblastoma using an orally-bioavailable CDK2/9 inhibitor

| PRJNA527249 | 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

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 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:Neuroblastoma is a common solid tumor that accounts for 15% of cancer deaths in children and amplification of the MYCN oncogene is the most common genomic alteration in aggressive tumors. Although MYCN is expressed as a tumor-specific oncoprotein in poor-outcome neuroblastoma, making it a therapeutic target of great potential importance, no drugs with significant activity against MYCN or MYC are available for clinical use. The aim of this study was to explore the sensitivity of neuroblastoma cells in vitro and in vivo to the tri-substituted purine CDK inhibitors, CYC065, chemical analogues of seliciclib, (Cyclacel Ltd).

2020-08-01 | GSE89197 | GEO

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