A Synergistic Combination Against Chronic Myeloid Leukemia: An Intra-molecular Mechanism of Communication in BCR-ABL1 Resistance
- PMID: 30877503
- DOI: 10.1007/s10930-019-09820-z
A Synergistic Combination Against Chronic Myeloid Leukemia: An Intra-molecular Mechanism of Communication in BCR-ABL1 Resistance
Abstract
The constitutive BCR-ABL1 active protein fusion has been identified as the main cause of chronic myeloid leukemia. The emergence of T334I and D381N point mutations in BCR-ABL1 confer drug resistance. Recent experimental studies show a synergistic effect in suppressing this resistance when Nilotinib and Asciminib are co-administered to target both the catalytic and allosteric binding site of BCR-ABL1 oncoprotein, respectively. However, the structural mechanism by which this synergistic effect occurs has not been clearly elucidated. To obtain insight into the observed synergistic effect, molecular dynamics simulations have been employed to investigate the inhibitory mechanism as well as the structural dynamics that characterize this effect. Structural dynamic analyses indicate that the synergistic binding effect results in a more compact and stable protein conformation. In addition, binding free energy calculation suggests a dominant energy effect of nilotinib during co-administration. van der Waals energy interactions were observed to be the main energy component driving this synergistic effect. Furthermore, per-residue energy decomposition analysis identified Glu481, Ser453, Ala452, Tyr454, Phe401, Asp400, Met337, Phe336, Ile334, And Val275 as key residues that contribute largely to the synergistic effect. The findings highlighted in this study provide a molecular understanding of the dynamics and mechanisms that mediate the synergistic inhibition in BCR-ABL1 protein in chronic myeloid leukemia treatment.
Keywords: Allosteric inhibitor; Asciminib (ABL001); BCR–ABL1; CML; Molecular dynamics; Mutation; Nilotinib.
Similar articles
-
The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1.Nature. 2017 Mar 30;543(7647):733-737. doi: 10.1038/nature21702. Epub 2017 Mar 22. Nature. 2017. PMID: 28329763
-
Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants.Cancer Cell. 2019 Oct 14;36(4):431-443.e5. doi: 10.1016/j.ccell.2019.08.004. Epub 2019 Sep 19. Cancer Cell. 2019. PMID: 31543464 Free PMC article.
-
The Perplexity of Synergistic Duality: Inter-molecular Mechanisms of Communication in BCR-ABL1.Anticancer Agents Med Chem. 2019;19(13):1642-1650. doi: 10.2174/1871520619666190620120144. Anticancer Agents Med Chem. 2019. PMID: 31250767
-
The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase.Leuk Res. 2020 Nov;98:106458. doi: 10.1016/j.leukres.2020.106458. Epub 2020 Sep 29. Leuk Res. 2020. PMID: 33096322 Review.
-
Development of asciminib, a novel allosteric inhibitor of BCR-ABL1.Crit Rev Oncol Hematol. 2022 Mar;171:103580. doi: 10.1016/j.critrevonc.2022.103580. Epub 2022 Jan 10. Crit Rev Oncol Hematol. 2022. PMID: 35021069 Review.
Cited by
-
New ABL1 Kinase Domain Mutations in BCR::ABL1-Positive Acute Lymphoblastic Leukemia.Cancer Med. 2024 Oct;13(20):e70317. doi: 10.1002/cam4.70317. Cancer Med. 2024. PMID: 39440695 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous