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

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

PROVIDER: PRJNA817156 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23470346.fastq.gz	Fastqsanger.gz
	SRR23470347.fastq.gz	Fastqsanger.gz
	SRR23470348.fastq.gz	Fastqsanger.gz
	SRR23470349.fastq.gz	Fastqsanger.gz
	SRR23470350.fastq.gz	Fastqsanger.gz

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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 (ChIP-seq)

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

| PRJNA817164 | ENA

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 (ChIP-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 | GSE225339 | GEO

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

2023-02-16 | GSE225342 | GEO

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

Project description:Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded 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 biological characterization revealed that BBC1115 binds to BET proteins, including BRD4, and suppresses aberrant cell fate programs. Phenotypically, BBC1115-mediated BET inhibition impaired proliferation in acute myeloid leukemia, pancreatic, colorectal, and ovarian cancer cells in vitro. Moreover, intravenous administration of BBC1115 inhibited subcutaneous tumor xenograft growth with minimal toxicity and favorable pharmacokinetic properties in vivo. Since epigenetic regulations are ubiquitously distributed across normal and malignant cells, it will be critical to evaluate if BBC1115 affects normal cell function. Nonetheless, our study shows 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.

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Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.

Project description:BRDT, BRD2, BRD3, and BRD4 comprise the bromodomain and extraterminal (BET) subfamily which contain two similar tandem bromodomains (BD1 and BD2). Selective BD1 inhibition phenocopies effects of tandem BET BD inhibition both in cancer models and, as we and others have reported of BRDT, in the testes. To find novel BET BD1 binders, we screened >4.5 billion molecules from our DNA-encoded chemical libraries with BRDT-BD1 or BRDT-BD2 proteins in parallel. A compound series enriched only by BRDT-BD1 was resynthesized off-DNA, uncovering a potent chiral compound, CDD-724, with >2,000-fold selectivity for inhibiting BRDT-BD1 over BRDT-BD2. CDD-724 stereoisomers exhibited remarkable differences in inhibiting BRDT-BD1, with the R-enantiomer (CDD-787) being 50-fold more potent than the S-enantiomer (CDD-786). From structure–activity relationship studies, we produced CDD-956, which maintained picomolar BET BD1 binding potency and high selectivity over BET BD2 proteins and had improved stability in human liver microsomes over CDD-787. BROMOscan profiling confirmed the excellent pan-BET BD1 affinity and selectivity of CDD-787 and CDD-956 on BD1 versus BD2 and all other BD-containing proteins. A cocrystal structure of BRDT-BD1 bound with CDD-956 was determined at 1.82 Å and revealed BRDT-BD1–specific contacts with the αZ and αC helices that explain the high affinity and selectivity for BET BD1 versus BD2. CDD-787 and CDD-956 maintain cellular BD1-selectivity in NanoBRET assays and show potent antileukemic activity in acute myeloid leukemia cell lines. These BET BD1-specific and highly potent compounds are structurally unique and provide insight into the importance of chirality to achieve BET specificity.

| S-EPMC9295786 | biostudies-literature

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]

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]

2023-08-14 | GSE188437 | GEO