Histone Methyltransferase Inhibitors: Novel Epigenetic Agents for Cancer Treatment

EPIGENETICS IS DEFINED AS HERITABLE CHANGES IN GENE ACTIVITY AND EXPRESSION THAT OCCUR WITHOUT ALTERATION IN DNA SEQUENCE. THE GENE TRANSCRIPTION IS STRICTLY CORRELATED TO CHROMATIN STRUCTURE, WHICH COULD UNDERGO COVALENT MODIFICATIONS OF HISTONES INVOLVING ACETYLATION, METHYLATION, PHOSPHORYLATION AND UBIQUITINATION. ALTERATIONS IN HISTONES ARE IMPLICATED IN MANY DISEASES, INCLUDING CANCER, BY LEADING TO TUMOR SUPPRESSOR SILENCING OR PRO-APOPTOTIC PROTEINS DOWNREGULATION. ALTHOUGH POST-TRANSLATIONAL ADDN. OF ME GROUPS TO THE HISTONE LYSINE HAS BEEN DISCOVERED THREE DECADES AGO, THE IMPORTANCE OF THIS EPIGENETIC MODIFICATION HAS EMERGED ONLY IN THE LAST FEW YEARS. THENCEFORWARD HISTONE METHYLTRANSFERASE INHIBITORS HAVE BEEN DEVELOPED AS POTENTIAL THERAPEUTIC CANCER AGENTS. IT SHOULD NOT BE LONG BEFORE SOME SELECTIVE INHIBITORS MAKE THEIR WAY INTO CLIN. TRIALS. THIS REVIEW IS MAINLY FOCUSED ON THE EVOLUTION IN THE DEVELOPMENT OF NEW EPIGENETIC MODIFIER MOLS. MODULATING HISTONE MARKS.

Epigenetics is defined as heritable changes in gene activity and expression that occur without alteration in DNA sequence. The gene transcription is strictly correlated to chromatin structure, which could undergo covalent modifications of histones involving acetylation, methylation, phosphorylation and ubiquitination. Alterations in histones are implicated in many diseases, including cancer, by leading to tumor suppressor silencing or pro-apoptotic proteins downregulation. Although post-translational addition of methyl groups to the histone lysine has been discovered three decades ago, the importance of this epigenetic modification has emerged only in the last few years. Thenceforward histone methyltransferase inhibitors have been developed as potential therapeutic cancer agents. It should not be long before some selective inhibitors make their way into clinical trials. This review is mainly focused on the evolution in the development of new epigenetic modifier molecules modulating histone marks.