Identification of Potent Inhibitors for Resistant Form of Chronic Myelogenous Leukaemia (CML)

The BCR-ABL protein is the causative agent in the pathogenesis of chronic myeloid leukemia (CML). Although there are several drugs in the market which inhibit BCR-ABL efficiently there are some cases of resistance1. Imatinib2,3, nilotinib3,4, bosutinib4 ,dasatinib5, bafetinib6 are approved tyrosine kinase inhibitors (TKI’s) and more recently, ponatinib was approved TKI which is shown to bind and inhibit the imatinib resistant BCR-ABL (T315I mutant). Ponatinib showed greater side effects like cardiovascular, cerebrovascular and peripheral vascular thrombosis, including fatal myocardial infarction and stroke7. Therefore, there is a need to identify new TKI’s which have greater inhibition capacity than marketed TKI’s with lesser side effects. In this current study, we have selected mutant BCR-ABL (T315I mutant) as a target protein which constitutes 20% of all mutations and screened several small molecule libraries to investigate the potential drug like compound against the BCR-ABL. Potential drug candidates were further examined for their druggability, stability and binding efficacy using computational approaches. Our investigation showed a group of select lead compounds exhibits promising binding affinity than the existing drugs such as ponatinib, imatinib, dasatinib, nilotinib, bosutinib, bafetinib that may be considered.