Nilotinib kinase activation

Chronic myelogenous leukemia Translocation BCR-ABL BCR-ABL (tyrosine-kinase activity) Imatinib, Dasatinib, Nilotinib, Bosutinib... 

Several inhibitors of their tyrosine kinase activity (non-selective from one receptor to the other) are approved for cancer therapy (imatinib, erlotinib, sorafenib and smitinib) and many others are clinically studied (dasatinib, nilotinib, pazopanib, vatalanib, vandetanib...). 

The T3151 mutation has been consistently shown to retain resistance to both dasatinib and nilotinib, and to the other pyridopyrimidine derivatives previously described. These recently developed small-molecule inhibitors have a differential activity compared to IM that relates to several key structural elements of ABLl. The ABLl kinase domain is bound by IM only in its inactive confirmation (with the activation loop in the closed position) (55). Because the inactive confirmations of ABLl and SRC are distinct, IM is able to inhibit ABLl but not SRC. 

Increasing potency Designing to the active state of the kinase Avoiding interaction with the gatekeeper Nilotinib Dasatinib VX-680, danusertib... 

Kim MJ, Lee JW, Oh KS, Choi CS, Kim KH, Han WS, Yoon CN, Chung ES, Kim DH, Shin JG (2013) The tyrosine kinase inhibitor nilotinib selectively inhibits CYP2C8 activities in human liver micro-somes. Drug Metab Pharmacokinet 28 462—467... 

---