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The design and development of covalent protein-protein interaction inhibitors for cancer treatment.

ABSTRACT: Protein-protein interactions (PPIs) are central to a variety of biological processes, and their dysfunction is implicated in the pathogenesis of a range of human diseases, including cancer. Hence, the inhibition of PPIs has attracted significant attention in drug discovery. Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein. Evidence suggests that there is a reduced risk for the development of drug resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious diseases. Recent improvements in structural biology and chemical reactivity have enabled the design and development of potent and selective covalent PPI inhibitors. In this review, we will highlight the design and development of therapeutic agents targeting PPIs for cancer therapy.

SUBMITTER: Cheng SS

PROVIDER: S-EPMC7106679 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The design and development of covalent protein-protein interaction inhibitors for cancer treatment.

Cheng Sha-Sha SS Yang Guan-Jun GJ Wang Wanhe W Leung Chung-Hang CH Ma Dik-Lung DL

Journal of hematology & oncology 20200330 1

Protein-protein interactions (PPIs) are central to a variety of biological processes, and their dysfunction is implicated in the pathogenesis of a range of human diseases, including cancer. Hence, the inhibition of PPIs has attracted significant attention in drug discovery. Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein. Evidence suggests that there is a reduced risk for the devel ...[more]

PMID: 32228680

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Correction to: The design and development of covalent protein-protein interaction inhibitors for cancer treatment.

Project description:An amendment to this paper has been published and can be accessed via the original article.

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Recent applications of covalent chemistries in protein-protein interaction inhibitors.

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Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors.

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Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer.

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Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment.

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Development of potent and selective KDM5 covalent inhibitors

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

Design, Synthesis and Characterization of Covalent KDM5 Inhibitors.

Project description:Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub-family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites.

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Approach for the Design of Covalent Protein Kinase Inhibitors via Focused Deep Generative Modeling.

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Development of Macrocyclic PRMT5-Adaptor Protein Interaction Inhibitors.

Project description:The PRMT5-MEP50 methyltransferase is a major target for anticancer drug discovery, and modulators of its interactions with different regulatory proteins are in high demand because they modulate PRMT5 substrate selectivity. We describe a strategy for the development of a PRMT5/adaptor protein PPI inhibitor, which includes the design and synthesis of macrocyclic peptides based on the motif for the interaction of PRMT5 with its adaptor protein RioK1. After the initial exploration of different macrocycle sizes and cyclization linkages, analysis of a peptide library identified hot spots for the variation of the amino acid structure. The incorporation of nonproteinogenic amino acids into the macrocyclic peptide led to a potent cyclic PRMT5 binding peptide (Ki = 66 nM), which selectively inhibits the interaction of PRMT5 with the adaptor proteins RioK1 and pICln (IC50 = 654 nM) but not with the alternative adaptor protein MEP50. The inhibitor is a promising tool for further biological investigation of this intriguing protein interface.

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