表观遗传突变的小分子抑制剂作为骨髓增生异常综合征的引人注目的药物靶标

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

Volume: 17 Issue: 7

关键词: 表观遗传突变，非编码RNA，骨髓增生异常综合征，AML，小分子抑制剂，药物靶标。

摘要: 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.

Cite this article as:

Small-molecule Inhibitors of Epigenetic Mutations as Compelling Drugtargets for Myelodysplastic Syndromes, Current Cancer Drug Targets 2017; 17 (7) . https://dx.doi.org/10.2174/1568009617666170330145002

DOI https://dx.doi.org/10.2174/1568009617666170330145002	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576