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BCR‐ABL residues interacting with Ponatinib are critical to preserve the tumorigenic potential of the oncoprotein (59.6)
Author(s) -
Romano Chiara,
Buffa Pietro,
Pandini Alessandro,
Massimino Michele,
Tirrò Elena,
Di Raimondo Francesco,
Manzella Livia,
Fraternali Franca,
Vigneri Paolo
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.59.6
Subject(s) - ponatinib , dasatinib , tyrosine kinase , protein kinase domain , imatinib , abl , myeloid leukemia , cancer research , mutant , chemistry , tyrosine , kinase , point mutation , biology , sh3 domain , biochemistry , microbiology and biotechnology , signal transduction , gene
Chronic Myeloid Leukemia patients that fail Tyrosine Kinase Inhibitors (TKIs) often present mutations in the BCR‐ABL catalytic domain. We noticed a lack of substitutions involving four amino acids (E286, M318, I360 and D381) that form hydrogen bonds with Ponatinib. We therefore introduced mutations in each of these residues either preserving or altering their physico‐chemical properties. We found that E286, M318, I360 and D381 are dispensable for ABL and BCR‐ABL protein stability but are critical to preserve catalytic activity. Indeed, only a “conservative” I360T substitution retained kinase proficiency and transforming potential. Molecular Dynamics simulations of BCR‐ABLI360T revealed differences in both helix‐αC dynamics and protein correlated motions consistent with a modified ATP binding pocket. Nevertheless, this mutant remained sensitive to Ponatinib, Imatinib and Dasatinib. These results suggest that changes in the four BCR‐ABL residues described here would be selected against by a lack of kinase activity or by maintained responsiveness to TKIs. Interestingly, amino acids equivalent to those identified in BCR‐ABL are conserved in 51% of human tyrosine kinases. Hence, these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.