Oligomerization inhibition, combined with allosteric inhibition, abrogates the transformation potential of T315I-positive BCR/ABL

Mian, A A, Oancea, C, Zhao, Z, Ottmann, O G ORCID: https://orcid.org/0000-0001-9559-1330 and Ruthardt, M ORCID: https://orcid.org/0000-0003-1021-3811 2009. Oligomerization inhibition, combined with allosteric inhibition, abrogates the transformation potential of T315I-positive BCR/ABL. Leukemia 23 , 2242–2247. 10.1038/leu.2009.194

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Abstract

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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0887-6924
Date of Acceptance:	13 July 2009
Last Modified:	22 Feb 2024 15:45
URI:	https://orca.cardiff.ac.uk/id/eprint/166077

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