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Exploring the Allosteric Pathways of Asciminib in the Dual Inhibition of BCR-ABL1
Jie Ming1, Hongwei Gao1, Jiuyu Zhan1
1School of Life Science, Ludong University, Yantai 264025, China.
Abstract:
The BCR-ABL1 fusion protein is a critical therapeutic target in Chronic Myeloid Leukemia (CML). Current monotherapy approaches involve types of inhibitors that can be categorized into ATP competitive inhibitors and allosteric inhibitors. However, resistance mutations in the tyrosine kinase domain of BCR-ABL1 have limited the effectiveness of these drugs. Research indicates that dual inhibition of BCR-ABL1 by combining these two types of inhibitors effectively addresses the issue of drug resistance as there are no overlapping resistance mechanisms. However, the underlying reasons for the observed synergistic effects have not yet been thoroughly elucidated. In this study, we employed molecular dynamics simulation to observe the synergistic interactions of BCR-ABL1 by the allosteric inhibitor asciminib and ATP competitive inhibitors nilotinib and ponatinib. Our study reveals that when asciminib binds to BCR-ABL1, nilotinib and ponatinib exhibit more substantial binding stability compared to monotherapy. At the atomic level, we have elucidated the reasons for the enhanced binding affinity of nilotinib and ponatinib when using a co-inhibition therapy. Our study reveals the allosteric communication pathway between asciminib and ponatinib, providing more detailed insights into the effectiveness of combination therapy. These findings provide valuable insights into combination therapies, aiding in the rational use of medications and guiding the design of novel inhibitors.
Insights
Dual inhibition targeting BCR-ABL1 with asciminib and other inhibitors enhances drug stability and binding affinity. This combination therapy overcomes resistance mutations in Chronic Myeloid Leukemia (CML) by revealing allosteric communication pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- BCR-ABL1 fusion protein is a key target in Chronic Myeloid Leukemia (CML).
- Monotherapies (ATP-competitive and allosteric inhibitors) face resistance due to BCR-ABL1 mutations.
- Dual inhibition strategies show promise in overcoming drug resistance.
Purpose of the Study:
- To elucidate the synergistic mechanisms of dual inhibition therapy for BCR-ABL1.
- To investigate the atomic-level interactions between asciminib, nilotinib, and ponatinib.
- To understand the allosteric communication pathways involved in combination therapy.
Main Methods:
- Molecular dynamics simulations were used to model BCR-ABL1 interactions.
- Simulations analyzed the binding stability and affinity of inhibitors in monotherapy versus combination therapy.
- Allosteric communication pathways were identified at the atomic level.
Main Results:
- Co-inhibition with asciminib and ATP-competitive inhibitors (nilotinib, ponatinib) significantly enhanced binding stability.
- Atomic-level analysis revealed mechanisms for increased binding affinity in combination therapy.
- A novel allosteric communication pathway between asciminib and ponatinib was elucidated.
Conclusions:
- Dual inhibition of BCR-ABL1 with asciminib and ATP-competitive inhibitors offers synergistic effects.
- Understanding these synergistic interactions provides insights into rational drug design and combination therapy strategies.
- This study aids in optimizing CML treatment by guiding the development of novel inhibitors.
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