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A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo [RNA-seq]

ABSTRACT: We hypothesised that PI3K and BET inhibition would synergise in the context of MYC-dysregulation and overcome resistance to single-target inhibition. We then synthesised a series of chimeric molecules linking BET- and PI3K-selective pharmacophores, including our lead molecule, 18D(S). RNA-Seq profiling following acute 18D(S) treatment demonstrated robust transcriptional modulation with concomitant BET and PI3K inhibitory signatures. Our data provides proof-of-concept for the design of potent PI3K- and BET-inhibitors, providing ‘synergy in a single molecule’.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188437 | GEO | 2023/08/14

REPOSITORIES: GEO

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A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo [scRNA-seq]

Project description:We hypothesised that PI3K and BET inhibition would synergise in the context of MYC-dysregulation and overcome resistance to single-target inhibition. We then synthesised a series of chimeric molecules linking BET- and PI3K-selective pharmacophores, including our lead molecule, 18D(S). RNA-Seq profiling following acute 18D(S) treatment demonstrated robust transcriptional modulation with concomitant BET and PI3K inhibitory signatures. Our data provides proof-of-concept for the design of potent PI3K- and BET-inhibitors, providing ‘synergy in a single molecule’.

2023-09-07 | GSE242465 | GEO

A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo [ChIP-seq]

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A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo

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

2023-08-14 | GSE188443 | GEO

Therapeutic targeting of GCB- and ABC-DLBCL by rationally designed BCL6 inhibitor

Project description:Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands.

2016-10-12 | GSE80351 | GEO

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