leaving efficacy the same or even slightly greater. Finally to improve the hydrogen bonding of the piperazine ring of imatinib with Ile-360 and His-361, pyrrolidine and azetidine derivatives were introduced. The most promising substance from these final modifications was labeled NS-187. Binding 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 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