Study of Combination Inhibitor Molecules against both Histone Deacetylase and Bcrabl using in Silico and in Vitro studies in cml cell lines

Abstract

Chronic Myeloid Leukemia (CML) is a type of leukemia, where there is a continuous proliferation of mature granulocytes and its precursors. An important breakthrough in the treatment of CML was the development of ATP competitive tyrosine kinase inhibitor (TKI) which can inhibit aberrant protein kinases. However, despite the promising initial response, development of point mutations in the BCR-ABL kinase domain led to Imatinib, Nilotinib and Dasatinib resistance and relapse in CML. The gate-keeper mutation Thr315Ileis one of the most threatening mutations thatprevent the binding of several TKI s by modifying the topology of the active site. Thus, more effective inhibitors of BCR-ABL are required to overcome the mutation newlineassociated resistance and inhibit disease progression. Multiple aberrant pathways are involved in the pathogenesis of cancer. Targeting these multiple pathways simultaneously proves to be more effective than targeting a single pathway. Multi-targeting strategy using more than one drug will lead to increased toxicity due to complex pharmacokinetics of two different drugs and also affects patient compliance. Therefore, a single hybrid molecule with the potential of newlinetargeting multiple aberrant pathways will be a better alternative to cancer therapy than newlinea combination of drugs. Along with BCR-ABL, HDAC plays a major role in continuous newlinesurvival and proliferation of CML cells. Therefore, in the present study, we designed newlinehybrid molecules by combining the key pharmacophores of Ponatinib and Vorinostat newlinethat can target BCR-ABL and HDAC mediated aberrant oncogenic pathways and newlinethereby accelerating CML cell death. newlineA set of 16 hybrid molecules was designed by combining the important newlinepharmacophores of Ponatinib (target BCR-ABL) and Vorinostat (target HDAC) using newlinebiocompatible linkers of different lengths and types. Best hybrid molecules were newlineselected using a Virtual Screening (VS) strategy based on enzyme inhibitory activity, newlineADMET properties and binding affinity towards BCR-ABL and HDAC.Chemoinformatics ...