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

Author(s): Bani Bandana Ganguly*

Journal Name: Current Cancer Drug Targets

Volume 17 , Issue 7 , 2017

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Graphical 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.

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Article Details

Year: 2017
Published on: 08 August, 2017
Page: [586 - 602]
Pages: 17
DOI: 10.2174/1568009617666170330145002
Price: $65

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