Development of potent and selective KDM5 covalent inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA486160 | ENA |
REPOSITORIES: ENA
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Project description:Histone lysine demethylase (KDMs) are involved in the dynamic regulation of gene expression by reversible regulation of the methylation levels on lysine residues in histone tails. Among the KDMs, the jumonji (JmjC)-domain-containing KDMs (KDM2-7) are Fe(II), 2- OG (α-ketoglutarate) and molecular oxygen-dependent enzymes that employ an oxygenase mechanism to demethylate specific methylation states at various histone sites. KDMs play a critical role in several biological processes such as cell differentiation, inflammation, cancer progression and resistance. Achieving selectivity over the different families of KDMs has been a major challenge. Here we report potent and selective KDM5 covalent inhibitors designed to target a cysteine residue only present in the KDM5 sub-family. In vitro assays show that compounds are selective for the KDM5 sub-family, showing potencies in the low nanomolar range, with higher affinity for KDM5A/B. The covalent binding to the targeted proteins was proved by MS. A kinetic approach was studied in order to describe the components of overall inhibitor potency (reversible binding and chemical reactivity), showing a time-dependent decrease of IC50 values for irreversible inhibition. Additional 2-OG competition assays show that compounds were non 2-OG competitive and target engagement and ChIPs-seq assays showed that the compounds inhibited the KDM5 members in cells in the low micromolar and they induce a global increase of the H3K4Me3 mark.
2018-12-10 | GSE118589 | GEO
Project description:Identification of covalent small-molecule inhibitors of STING
2018-05-02 | GSE113933 | GEO
Project description:Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme (DUB) that is very highly expressed in human brain. UCHL1 has been proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis, however bona fide molecular functions of UCHL1 are yet to be elucidated. Herein we characterize a potent and selective inhibitor and activity-based probe (IMP-1710) for UCHL1 based on a covalent inhibitor scaffold, and its application to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration, and we show that a previously claimed UCHL1 inhibitor (LDN-57444) fails to engage UCHL1 in cells. We further demonstrate that potent UCHL1 inhibitors selectively block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis (IPF), supporting a potential therapeutic role for UCHL1 inhibition.
2020-11-12 | PXD015825 | Pride
Project description:Activating mutations in ERBB receptors act as oncogenes in non-small cell lung cancer (NSCLC). Besides the more prevalent epidermal growth factor receptor (EGFR) activating mutations, oncogenic variants in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of NSCLC patients. HER2 oncogenic mutations in NSCLC predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinically approved and currently tested tyrosine kinase inhibitors are limited by either insufficient potency on exon 20 altered HER2 and/or their insufficient selectivity against EGFR wild type (EGFR WT) – a major cause of dose limiting toxicity. We report herein the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing EGFR WT. The new inhibitors presented in this study reduce tumor cell survival and proliferation in vitro, and result in regressions in in vivo preclinical xenograft models of HER2 exon 20 mutant NSCLC as well as inhibition of downstream signaling. Our results suggest that HER2 exon 20 insertion driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing EGFR WT. The new inhibitors described in this study pave the way for testing potent HER2 selective inhibitors in HER2 mutant NSCLC patients and may offer an additional therapeutic option for these patients.
2022-03-19 | GSE181673 | GEO
Project description:Identification of covalent small-molecule inhibitors of STING
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Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), to cells treated with ND-2158 for the indicated times (Cy5).
2015-11-01 | E-GEOD-63029 | biostudies-arrayexpress
Project description:Prostate cancer (PCa) affects over 250,000 men in the US. Androgen Receptor (AR) signaling inhibitors are the mainstay therapeutics for PCa. Advanced PCa that expresses AR splice variants (AR-SVs) does not respond to current therapeutic strategies. In this manuscript, we uncovered the physicochemical properties of the intrinsically-disordered transactivation domain of AR and AR-SV and developed novel AR irreversible covalent antagonists (SARICA) to the transactivation domain for the treatment of advanced PCa. SARICAs were also used to identify a potential binding region in the AR and AR-SV transactivation domain.
2022-12-31 | GSE215335 | GEO
Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer.
2015-11-01 | GSE63029 | GEO
Project description: Not available
| S-EPMC6391970 | biostudies-literature
Project description:Alterations in the histone methylation profiles are observed in various types of cancer and targeting of this epigenetic process has therapeutic potential. Here we provide proof-of-principle that pharmacological targeting of KDM5 histone-demethylases is a new strategy for the personalized treatment of HER2-positive breast cancer. This analysis demonstrates that cells characterized by HER2-positivity are particularly sensitive to KDM5 inhibition. The results are confirmed in an appropriate in vivo model with a close structural analogue (KDM5-inh1A). In selected HER2-positive breast cancer cells, we demonstrate synergistic interactions between KDM5-inh1 and HER2-targeting agents (trastuzumab and lapatinib). In addition, HER2-positive cell lines showing innate/acquired resistance to trastuzumab show sensitivity to KDM5-inh1. The levels of KDM5A/B/C proteins, which are selectively targeted by the agent, have no significant association with KDM5-inh1 responsiveness across our panel of breast cancer cell lines, suggesting the existence of other determinants of sensitivity. Using RNA-sequencing data of the breast cancer cell lines, we generate a gene-expression model, consisting of fifteen genes, which is a robust predictor of KDM5-inh1 sensitivity. In a test set of breast cancers, this model correctly predicts sensitivity to the compound in a large fraction of HER2+ tumors. In conclusion, KDM5 inhibition has potential in the treatment of HER2+ breast cancer and our gene-expression model can be developed into a diagnostic tool to select patients who may benefit from treatments based on KDM5-inhibitors.
2019-02-01 | E-MTAB-7433 | biostudies-arrayexpress