Speaker
Description
Background: Aberrant and proliferative expression of the oncogene BCR-ABL in bone
marrow cells is one of the prime causes of chronic myeloid leukemia (CML). It has been
established that the tyrosine kinase domain of the BCR-ABL protein is a potential therapeutic
target for the treatment of CML. Although first and second line inhibitors against the enzyme
are available, recent studies have indicated that monotherapeutic resistance has become an
aggrieved challenge.
Objective/Methods: In recent studies, the dual inhibition of BCR-ABL by Nilotinib and
Asciminib was shown to overcome drug resistance. This prompted us to investigate, with the
use of computational tools, the molecular dynamics behind this novel drug combination.
Results: Conformational ensemble analysis presented a sustained inactive protein, as the
activation loop, inclusive of the characteristic Tyr257, remained in an open position due to
the unassailable binding of Asciminib at the allosteric site. Nilotinib also indicated more
propitious binding at the catalytic site in the presence of Asciminib, thus exposing new
avenues in treating Nilotinib-resistance. This was in countenance with intermolecular
hydrogen bond interactions with key binding site residues GLU399, Asn259 and Thr252.
Conclusion: The investigations carried out in this study give rise to new possibilities in the
treatment of resistance in CML, as well as assisting in the design of novel and selective
inhibitors as dual anti-cancer drugs.
