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Accueil du site > Animations Scientifiques > Séminaires 2007 > Small Molecule Modulators of Chromatin Modifying Enzymes : To Probe Eukaryotic Transcription and To Target Diseases

Small Molecule Modulators of Chromatin Modifying Enzymes : To Probe Eukaryotic Transcription and To Target Diseases

Orateur :

Tapas K. Kundu, Transcription an Disease Laboratory and, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India

Salle :


Sujet :

Human genes are organized into a highly compact dynamic nucleoprotein complex called chromatin, which consists of histones and associated non-histone proteins. Though apparently repressive, the precise organization of chromatin is essential for the entire DNA-templated phenomenon inside the cell. Alteration in chromatin organization modulates the expression of underlying genes. The post-transitional modification (eg. reversible acetylation, methylation and phosphorylation) of chromatin proteins plays crucial roles in the dynamic organization chromatin template for all he cellular phenomenon including transcription. Dysfunction of these enzymes is often associated with several diseases like Cancer, Asthma, Diabetes and several Neurodegenerative disorders. Small molecule modulators of HATs, HDACs, and HMTases thus are new potential therapeutic molecules. We have discovered several small molecule modulators of acetyltransferases, which include anacardic acid, garcinol, curcumin, as HAT inhibitors and CTPB as activator. CTPB is the only known small molecule HAT activator histone acetyltransferases, which is specific for the p300 HAT activity.

Most recently based on the natural cell permeable HAT inhibitor we have synthesized couple of p300 specific cell permeable inhibitors which significantly non-toxic as compared to parent compound. We have recently found a potent and specific inhibitor of histone arginine methyltransferase, CARM1. The role of this compound on methylation dependent activation of p53 responsive genes and its functional consequence is being investigated. The significance of these small molecular modulators is immense with respect to the as yet unexplored field of EPIGENETICS based drugs. These compounds would be useful as biological switching molecules for probing into the role of HATS/HDACs/HMTases in gene regulation, and may also serve as new chemical entities for the development of new drugs.

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