Dataset Information

Discovery of a chemical probe for PRDM9.

ABSTRACT: PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80?±?16?nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

SUBMITTER: Allali-Hassani A

PROVIDER: S-EPMC6917776 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Discovery of a chemical probe for PRDM9.

Allali-Hassani Abdellah A Szewczyk Magdalena M MM Ivanochko Danton D Organ Shawna L SL Bok Jabez J Ho Jessica Sook Yuin JSY Gay Florence P H FPH Li Fengling F Blazer Levi L Eram Mohammad S MS Halabelian Levon L Dilworth David D Luciani Genna M GM Lima-Fernandes Evelyne E Wu Qin Q Loppnau Peter P Palmer Nathan N Talib S Zakiah A SZA Brown Peter J PJ Schapira Matthieu M Kaldis Philipp P O'Hagan Ronan C RC Guccione Ernesto E Barsyte-Lovejoy Dalia D Arrowsmith Cheryl H CH Sanders John M JM Kattar Solomon D SD Bennett D Jonathan DJ Nicholson Benjamin B Vedadi Masoud M

Nature communications 20191217 1

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC<sub>50</sub>: 80 ± 16 nM), selective a ...[more]

PMID: 31848333

Similar Datasets

Project description:During the past two decades, the world has witnessed the emergence of various SARS-CoV-2 variants with distinct mutational profiles influencing the global health, economy, and clinical aspects of the COVID-19 pandemic. These variants or mutants have raised major concerns regarding the protection provided by neutralizing monoclonal antibodies and vaccination, rates of virus transmission, and/or the risk of reinfection. The newly emerged Omicron, a genetically distinct lineage of SARS-CoV-2, continues its spread in the face of rising vaccine-induced immunity while maintaining its replication fitness. Efforts have been made to improve the therapeutic interventions and the FDA has issued Emergency Use Authorization for a few monoclonal antibodies and drug treatments for COVID-19. However, the current situation of rapidly spreading Omicron and its lineages demands the need for effective therapeutic interventions to reduce the COVID-19 pandemic. Several experimental studies have indicated that the FDA-approved monoclonal antibodies are less effective than antiviral drugs against the Omicron variant. Thus, in this study, we aim to identify antiviral compounds against the Spike protein of Omicron, which binds to the human angiotensin-converting enzyme 2 (ACE2) receptor and facilitates virus invasion. Initially, docking-based virtual screening of the in-house database was performed to extract the potential hit compounds against the Spike protein. The obtained hits were optimized by DFT calculations to determine the electronic properties and molecular reactivity of the compounds. Further, MD simulation studies were carried out to evaluate the dynamics of protein-ligand interactions at an atomistic level in a time-dependent manner. Collectively, five compounds (AKS-01, AKS-02, AKS-03, AKS-04, and AKS-05) with diverse scaffolds were identified as potential hits against the Spike protein of Omicron. Our study paves the way for further in vitro and in vivo studies.

Dataset Information

Discovery of a chemical probe for PRDM9.

Publications

Discovery of a chemical probe for PRDM9.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets