PCV - Programme interdiciplinaire en physique et chimie du vivant

Insights into CARM1 methylation: design of selective inhibitors and peptide mimics. A structure based approach – CARM1

Submission summary

Post-translational methylation of arginine is a widespread epigenetic modification found in eukaryotes that is catalyzed by the protein arginine methyltransferases (PRMTs). PRMTs have been implicated in a variety of biological processes, such as regulation of transcription, translation and DNA repair. At least nine members of PRMTs (PRMT1 to PRMT9) have been identified and classified into two main classes. Coactivator-associated arginine methyltransferase 1 (CARM1, also known as PRMT4) was identified as an enhancer of the transcriptional activation by several nuclear hormone receptors. CARM1 is a crucial protein involved in many biological processes including the regulation of chromatin structure and transcription via methylation of histones and many transcriptional cofactors. As such, understanding the detailed mechanism of action of this protein at the structural level is important and has implications ranging from pure structural information to potential ways of regulating gene expression via inhibitor design. Despite numerous structural information available on CARM1 and on several other PRMTs, the binding mode of substrates prior to methylation or the binding mode of product subsequent to methylation remains to be visualized and understood at the atomic level. The project described here will combine chemistry, molecular modeling and X-ray crystallography with the aim to address two challenges in the field. The first one is to understand at the atomic level the mode of binding of substrate/product arginine-containing peptides, reflecting states prior and subsequent to methylation. We propose to solve this challenge by synthesizing analogs or mimics of the transition state of the reaction where the substrate/product will be linked to the S-adenosyl-L-methionine cofactor. Enzymes involved in epigenetic modifications represent new targets for which compounds can be developed and that can be exploited to provide new therapies against cancer. CARM1 has been shown for example to be over-expressed in breast tumors and in hormone dependant prostate tumors. The inhibition of both PRMT1 and CARM1 can suppress estrogen and androgen-receptor mediated transcriptional activation. Therefore, CARM1 and other PRMTs are likely to provide useful targets in the design of new anticancer agents. Small molecule inhibitors of histone arginine methyltranferases have already been described and are promising lead compounds for future drug development. However, current methyl transferase inhibitors display limited specificity, indiscriminately targeting all enzymes that use SAM as methyl donor. Moreover, the mode of binding of such starting compounds remains unknown and required further structural investigations. The second challenge of this project will be to design, synthesize and improve, by structure based-drug design, compounds that can inhibit CARM1 methylation activity. Based on several crystal structures of CARM1 determined in our team, our first aim is to propose modifications of existing compounds to enhance their affinity towards CARM1. Combining chemistry and molecular modeling we then hope to discover compounds that have sufficient affinity to form stable complexes suitable for X-ray diffraction studies. A first crystal structure of CARM1 in the presence of promising PRMT specific inhibitor will be a breakthrough in the field and will accelerate the development of better compounds.

Project coordination

Jean CAVARELLI (CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE - CERBM)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE - CERBM

Help of the ANR 450,000 euros
Beginning and duration of the scientific project: - 36 Months

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