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Functional Characterization of a Potent and Novel BET Inhibitor BBC1115 Identified from DNA-encoded Small Molecule Library Screening (ChIP-seq)

ABSTRACT: Functional Characterization of a Potent and Novel BET Inhibitor BBC1115 Identified from DNA-encoded Small Molecule Library Screening (ChIP-seq)

PROVIDER: PRJNA817164 | ENA |

REPOSITORIES: ENA

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Functional Characterization of a Potent and Novel BET Inhibitor BBC1115 Identified from DNA-encoded Small Molecule Library Screening

Project description:Functional Characterization of a Potent and Novel BET Inhibitor BBC1115 Identified from DNA-encoded Small Molecule Library Screening

| PRJNA817156 | ENA

Functional Characterization of a Potent and Novel BET Inhibitor BBC1115 Identified from DNA-encoded Small Molecule Library Screening (RNA-seq)

Project description:Functional Characterization of a Potent and Novel BET Inhibitor BBC1115 Identified from DNA-encoded Small Molecule Library Screening (RNA-seq)

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Functional Characterization of a Potent and Novel BET Inhibitor BBC1115 Identified from DNA-encoded Small Molecule Library Screening

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

2022-03-20 | GSE198843 | GEO

Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins (RNA-seq)

Project description:Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded small-molecule library (DEL) screening is a core platform technology increasingly used to identify drugs that bind to protein targets. Here, we use DEL screening against bromodomain and extra-terminal motif (BET) proteins to identify inhibitors with new chemotypes, and successfully identified BBC1115 as a selective BET inhibitor. While BBC1115 does not structurally resemble OTX-015, a clinically active pan-BET inhibitor, our intensive computational modeling and biological characterization revealed that BBC1115 binds to BET protein BRD4 and suppresses aberrant cell fate programs. Phenotypically, BBC1115-mediated BET inhibition impaired proliferation in acute myeloid leukemia, pancreatic, and colorectal cancer cells in vitro. Moreover, intravenous administration of BBC1115 inhibited subcutaneous pancreatic and colorectal cancer xenograft growth with minimal toxicity and favorable pharmacokinetic properties in vivo. Since epigenetic regulations are ubiquitously employed across normal and malignant cells, it will be critical to evaluate whether BBC1115 interferes with normal cellular functions. Nonetheless, our study implicates that integrating DEL-based small-molecule compound screening and multi-step biological validation represents a reliable strategy to discover new chemotypes with selectivity, efficacy, and safety profiles for targeting proteins involved in epigenetic regulation in human malignancies.

2023-02-16 | GSE225342 | GEO

Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins (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 [ChIP-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’.

2023-08-14 | GSE188442 | 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 [RNA-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 [scRNA-seq]

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Activity-Based DNA-Encoded Library Screening.

Project description:Robotic high-throughput compound screening (HTS) and, increasingly, DNA-encoded library (DEL) screening are driving bioactive chemical matter discovery in the postgenomic era. HTS enables activity-based investigation of highly complex targets using static compound libraries. Conversely, DEL grants efficient access to novel chemical diversity, although screening is limited to affinity-based selections. Here, we describe an integrated droplet-based microfluidic circuit that directly screens solid-phase DELs for activity. An example screen of a 67?100-member library for inhibitors of the phosphodiesterase autotaxin yielded 35 high-priority structures for nanomole-scale synthesis and validation (20 active), guiding candidate selection for synthesis at scale (5/5 compounds with IC50 values of 4-10 ?M). We further compared activity-based hits with those of an analogous affinity-based DEL selection. This miniaturized screening platform paves the way toward applying DELs to more complex targets (signaling pathways, cellular response) and represents a distributable approach to small molecule discovery.

| S-EPMC6786493 | biostudies-literature

Off-DNA DNA-Encoded Library Affinity Screening.

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