Oligomerization inhibition, combined with allosteric inhibition, abrogates the transformation potential of T315I-positive BCR/ABL.
The t(9;22) translocation leads to the formation of the chimeric bcr/abl fusion gene, which encodes the BCR/ABL fusion protein. In contrast to its physiological counterpart c-ABL, the BCR/ABL kinase is constitutively activated, inducing the leukemic phenotype. The N-terminus of c-ABL (Cap region) contributes to the regulation of its kinase function. It is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain known as the myristoyl-binding pocket in a process called 'capping', which results in an auto-inhibited conformation. Because the cap region is replaced by the N-terminus of BCR, the BCR/ABL 'escapes' this auto-inhibition. Allosteric inhibition by myristate 'mimics', such as GNF-2, is able to inhibit unmutated BCR/ABL, but not the BCR/ABL that harbors the 'gatekeeper' mutation T315I. In this study, we analyzed the possibility of increasing the efficacy of allosteric inhibition by blocking BCR/ABL oligomerization. We showed that inhibition of oligomerization was able to not only increase the efficacy of GNF-2 on unmutated BCR/ABL, but also overcome the resistance of BCR/ABL-T315I to allosteric inhibition. These results strongly suggest that the response to allosteric inhibition by GNF-2 is inversely related to the degree of oligomerization of BCR/ABL. In summary, our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants represented by the combination of oligomerization and allosteric inhibitors.
Department of Hematology, Goethe University, Klinikum der Goethe Universität Frankfurt, Theodor Stern Kai 7, Frankfurt, Germany.
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Mian
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Oancea
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Zhao
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Ottmann
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Ruthardt
D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats
C508526:GNF-2 compound; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl