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Small-molecule Inhibitors of Epigenetic Mutations as Compelling Drugtargets for Myelodysplastic Syndromes

[ Vol. 17 , Issue. 7 ]

Author(s):

Bani Bandana GangulyPages 586-602 (17)

Abstract:


Background: Involvement of mutations in epigenetic mechanism in the development of heterogeneous MDS and its evolution to AML has been understood with at least one mutation and median of 2-3 mutations of the landscapes of driver mutations in ~40 genes described in >90% MDS patients. Exclusivity and cooperating effects of mutations have directed therapeutic implementation with hypomethylating agents and identified a number of first-in-class small molecules as inhibitors of mutational expression. Preclinical and clinical trials have already been initiated for some synthetic and natural products and established proof-of-concept for mitigation of mutagenic effects.

Objective: The present review article entails the mutational signatures in DNA-methylation and hydroxymethylation, histone acetylation and Deacetylation, polycomb repressor complex (PRC2), and small molecule inhibitors of these mutational expressions.

Method: Information has been collected from the recently published literature available mainly through Google search in Medline and PubMed database. Special emphasis was paid on the literature available during 2009-2016.

Result: The up-to-date information accumulated on signature-mutations and their inhibitors has to integrate the function of clonal hematopoiesis of indeterminate potential (CHIP) and mutational complexities for re-defining MDS-genesis. Nevertheless, molecular understanding of MDS heterogeneity and its transformation to AML is expanding at fast pace with expanding knowledge on abundant non-coding RNAs (ncRNAs), which forms the basis of targeted drug-tailoring, and will further develop personalized medicines based on individual genetic blue-prints.

Conclusion: Mutation-specific targeted epigenetic drugs, which have already sensitized drug-makers and regulators, may promise attestation of ‘del5q and lenalidomide’-like specific drugs for every mutational signature independently or in combination with standard therapeutic elements used for MDS-management, and that will add to understand their antagonistic/synergistic effects.

Keywords:

Epigenetic mutations, non-coding RNAs, myelodysplastic syndromes, AML, small molecule inhibitors, drug targets.

Affiliation:

MGM Center for Genetic Research & Diagnosis, MGM New Bombay Hospital, Vashi sector 3, Navi Mumbai 400703

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