Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy
Bcr-Abl inhibitors led the way of targeted therapy epoch. Imatinib was the very first tyrosine kinase inhibitor to become discovered rich in specificity for Bcr-Abl protein caused by t(9, 22)-derived Philadelphia chromosome. Even though the specific targeting of this oncoprotein, several Bcr-Abl-dependent and Bcr-Abl-independent mechanisms of potential to deal with imatinib came about after becoming first-line therapy in chronic myelogenous leukemia (CML) treatment.Consequently, new specific drugs, namely dasatinib, nilotinib, bosutinib, and ponatinib, were rationally designed and approved for clinic to override resistances. Imatinib fine mechanisms of action have been elucidated to rationally develop individuals second- and third-generation inhibitors. Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to Danusertib reveal this subject. More lately, preclinical evidence on bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for much better inhibitors to become approved for clinic soon.Particularly, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.