The t(9;22) leads to the formation of the chimaeric bcr/abl fusion gene which encodes for the BCR/ABL fusion protein. In contrast to its physiological counterpart c-ABL, whose kinase activity is finely regulated by growth factors and other stimuli, BCR/ABL is constitutively activated. Thus it aberrantly activates down-stream signaling pathways inducing the leukemic phenotype 6. In the BCR/ABL, the N-terminus part of ABL is replaced by the N-terminus part of BCR. The N-terminus end (Cap region) of c-ABL, absent in BCR/ABL, is implicated in regulating the kinase function of ABL. The N-terminus of ABL is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain (Myristoyl binding pocket, MBP), a process called “capping” which turns c-ABL into an auto-inhibited conformation. BCR/ABL “escapes” this auto-inhibition, because the myristoylated N-terminus of ABL is lost by the fusion to BCR in the BCR/ABL fusion protein 8. In this project we provided the proof of principle of i.) an efficient drug design for compounds actively targeting the MBP of BCR/ABL; ii.) that allosteric inhibitors alone are able to inhibit the BCR/ABL-T315I, which is resistant against all molecular therapy approaches with the exception of the multitargeted AKI Ponatinib. Further we were able to show that BCR/ABL-T315I can be efficiently targeted by a combination of oligomerization inhibitors with the allosteric inhibitor GNF-2, which binds to the MBP 1. Moreover, we showed that GNF-2 regains activity against T315I mutation when used together with ATP-competitive inhibitors such as Nilotinib and Dasatinib9,12. We further optimized the computational drug design of MBP binders by additional docking strategies, tested more than 150 new compound for their inhibitory effects against the BCR/ABL-kinase and then further investigated in pre-clinical models of Ph+ leukemia. We developed model systems of Ph+ leukemia nearly aspects of clinically relevant aspects in vitro as well as in vivo for investigating mechanisms of mutational and not mutational resistance mechanisms as well as tor establishing novel therapy approaches for the treatment of both Ph+ CML and Ph+ ALL; iii.) we optimized response to allosteric inhibition by the combination with oligomerization inhibition10 using interfering peptides which were further optimized “in silico”; iv.) evidenced a strong allosteric inhibitory activity against ABL of the dual Met/Alk-inhibitor Crizotinib, developed for the treatment of lung cancer; v.) we disclosed the active principle of a natural mushroom extract able to target BCR/ABL-kinase.