Dasatinib is a drug of several generations

Dasatinib (Dasatinib) is a potent second-generation small molecule multi-target BCR-ABL kinase inhibitor, developed by Bristol Myers Squibb (Bristol Myers Squibb). This drug exerts greater in vitro activity than imatinib against unmutated ABL kinase. Dasatinib was originally developed as an inhibitor of Src family kinases such as Fyn, Yes, Src, and Lyk, but it also inhibits BCR-ABL, EphA2, platelet-derived growth factor receptor, and c-Kit. In addition, it binds to other tyrosine and serine/threonine kinases, such as mitogen-activated protein kinase and receptor tyrosine kinase, discoid domain receptor 1.

Dasatinib can inhibit the proliferation and kinase activity of imatinib-resistant wild-type andBCR-ABL mutant cell lines, except for cell lines carrying the T315I mutation. In vivo studies show that dasatinib is 325 times more potent than imatinib and 16 times more potent than nilotinib, another BCR-ABL kinase inhibitor. In mouse models, targeting unmutated BCR ABL. Dasatinib was shown to inhibit leukemia cell growth and extend survival of mice carrying wild-typeBCR ABL and M351T, but not the T315I mutant. Dasatinib is a bispecific Src and ABL inhibitor that inhibits both active and inactive conformations of ABL.

The activity of dasatinib against 18 imatinib-resistant BCR/ABL mutant strains was also studied clinically compared with two other TKIs (nilotinib and bosutinib). Dasatinib is more active than nilotinib against the 252 and 253 mutations common in imatinib-resistant patients. In addition, dasatinib is also active against the H396P/R mutation in the activation loop or F359F in the active site. The U.S. Food and Drug Administration (FDA)approved dasatinib for the treatment of imatinib-resistant or intolerant chronic phase, accelerated phase or blast phase chronic myeloid leukemia, as well as Ph chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant to previous treatments.