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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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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.

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

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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.

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