final modifications was labeled ns-187. binding bafetinib in its binding site due to the structural similarities of imatinib and bafetinib, their binding to bcr-abl is also quite similar. the only notable difference comes from the hydrophobic interaction between the trifluoromethyl group and the hydrophobic pocket created by ile-293, leu-298, leu-354, and val-379. this group can also be linked to bafetinib's specificity for lyn, as the binding site there is almost identical to that on bcr-abl. bafetinib has its place in tki therapy as it is effective both against most imatinib resistant mutations (not including t315i) and some dasatinib resistant mutations. bafetinib also has more affinity for bcr-abl than nilotinib (but less than dasatinib) but only targets bcr-abl and src family kinases lck and lyn; with unrivalled specificity which suggests the probability of fewer adverse effects. cytrx has bafetinib in phase ii clinical trial as a treatment for leukemia as of may 2010. 1,3,4 thiadiazole derivatives - substance 14 some interest has been with thiazol and thiadiazole derivatives and their ability to inhibit bcr-abl tks. development proposed binding site interactions of substance 14 one italian research group discovered through digital screening that commercially available thiadiazole derivatives displayed moderate inhibitory action on both abl and src kinases. using a 1,3,4 thiadiazol core and trying different groups or molecules on the benzene rings, several different substances with inhibitory properties were produced. the flexibility of the core allowed a number of conformations of the substances to bind to the atp site of the abl kinase, though all of them bound to the kinase's active form. further study of the binding showed that the position of the sulfur that binds to the toluene structure played an important role in regard to abl binding and also that only one of the nitrogen's one thiadiazole formed a hydrogen bond. furthermore, computer analysis of the structure showed the amide connected benzene-ketone could be substituted for a more favorable thiophene ring. though it has to be noted this analysis was done with comparing the crystal structure of abl and dasatinib, which is the inactive conformation of abl, the knowledge gathered from the docking and structure analysis led to identification of a compound, referred to as substance 14, with a high affinity to abl. binding the binding of substance 14 is partly similar to dasatinib, the aminothiazole segment of substance 14 makes a bi-dentate h-bonding interaction with the backbone co and nh of met-318 while the methoxy-benzene falls nicely into a hydrophobic pocket created by val 256, ala 253, lys 271 and ala 380. whilst the similar binding properties to those of dasatinib, suggests the possibility of producing bcr-abl tki's from thiazole cores is real, the question remains open whether this research will just lead to a dasatinib analog or a novel way to inhibit tks. others rebastinib (dcc-2036) also an inhibitor of tie-2 and vegfr-2. it has had a phase 1 clinical trial for leukemias (ph+ cml with t315i mutation). it is in a phase 1 clinical trial of combination therapy for metastatic breast cancer. asciminib (abl001) is an inhibitor of the abelson kinase targeting the myristoyl pocket to allosterically inhibit the enzyme. as of august 2020, it had completed a phase iii study in cml (ascembl) showing superior efficacy to bosutinib. summary drug structure h-bonds h-bonding amino acids binding confirmation discovery status as of 2017 imatinib (sti571) 6 met-318, thr-315, glu-286, asp-381, ile-380, his-361 inactive drug screening marketed as first line therapy nilotinib (amn107) 4 met-318, thr-315, glu-286, asp-381 inactive rational drug design marketed as second line therapy dasatinib (bms-345825) 3 met-318, thr-315 active rational drug design marketed as second line therapy bosutinib (ski-606) - - inactive rational drug design marketed as second line therapy ponatinib (ap-24534) 5 met-318, asp-381, glu-286, his-381, ile-380 inactive rational drug design marketed as second line therapy bafetinib (inno-406) 6 met-318, thr-315, glu-286, asp-381, his-361, ile-360 inactive rational drug design marketed as second line therapy current status - re ph+ cml imatinib remains a standard frontline tki. nilotinib and dasatinib are also approved by the fda as frontline drugs, in june and october 2010, respectively. four of these drugs, nilotinib, dasatinib, bosutinib and ponatinib are approved for the treatment of imatinib-resistant or intolerant cml. the first-line data for these compounds are encouraging and suggest that some or all of them may replace imatinib as a frontline standard tki in the future.