Advancements and Future Prospects in Molecular Targeted and siRNA Therapies for Chronic Myeloid Leukemia
Abstract
:1. Introduction
2. The Protein p210 BCR–ABL1 Is a Key Player in the Pathogenesis of CML
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- The N-terminal region possesses a coiled-coil oligomerization domain (CC) implicated in binding to proteins containing the Src-homology 2 domain.
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- A serine/threonine kinase domain capable of phosphorylating tyrosine residues, including tyrosine 117 (Y177).
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- A segment homologous to the Rho guanine nucleotide exchange factor (Rho-GEF).
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- A calcium-binding domain (CaLB).
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- A region resembling the Rac GTPase-activating protein (Rac-GAP).
3. Strategies for Inhibiting the Chimeric Protein BCR–ABL1
3.1. ATP-Competitive Inhibitors of BCR–ABL1
3.2. Allosteric Inhibitors of BCR–ABL1
3.3. Inhibition of the Chimeric Oncogene BCR–ABL1 Using siRNA
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug | Pharmacological Strategy for Inhibiting the BCR–ABL1 | Mechanism of Action | Activity against T315I Mutations | Clinical Status |
---|---|---|---|---|
First-line treatment | ||||
Imatinib (Gleevec; Novartis) | ATP-competitive inhibitor | first generation TKI | no | FDA approved |
Dasatinib (Sprycel; Bristol Myers Squibb) | ATP-competitive inhibitor | second-generation TKI | no | FDA approved |
Nilotinib (Tasigna; Novartis) | ATP-competitive inhibitor | second-generation TKI | no | FDA approved |
Bosutinib (Bosulif; Pfizer) | ATP-competitive inhibitor | second-generation TKI | no | FDA approved |
Ponatinib (Iclusig; Takeda) | ATP-competitive inhibitors | third-generation TKI | yes | FDA approved |
Asciminib (Scemblix; Novartis) | Allosteric inhibitor | targeting the ABL myristoyl pocket (STAMP) | yes | FDA approved |
Emerging Therapies | ||||
Radotinib | ATP-competitive inhibitors | second-generation TKI | no | NCT03722420 |
Flumatinib | ATP-competitive inhibitors | second-generation TKI | no | NCT02204644 |
Olverembatinib (HQP1351) | ATP-competitive inhibitors | third-generation TKI | yes | NCT05594758 |
Vodobatinib (K0706) | ATP-competitive inhibitors | third-generation TKI | yes | NCT02629692 |
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Vysochinskaya, V.; Dovbysh, O.; Gorshkov, A.; Brodskaia, A.; Dubina, M.; Vasin, A.; Zabrodskaya, Y. Advancements and Future Prospects in Molecular Targeted and siRNA Therapies for Chronic Myeloid Leukemia. Biomolecules 2024, 14, 644. https://doi.org/10.3390/biom14060644
Vysochinskaya V, Dovbysh O, Gorshkov A, Brodskaia A, Dubina M, Vasin A, Zabrodskaya Y. Advancements and Future Prospects in Molecular Targeted and siRNA Therapies for Chronic Myeloid Leukemia. Biomolecules. 2024; 14(6):644. https://doi.org/10.3390/biom14060644
Chicago/Turabian StyleVysochinskaya, Vera, Olesya Dovbysh, Andrey Gorshkov, Alexandra Brodskaia, Michael Dubina, Andrey Vasin, and Yana Zabrodskaya. 2024. "Advancements and Future Prospects in Molecular Targeted and siRNA Therapies for Chronic Myeloid Leukemia" Biomolecules 14, no. 6: 644. https://doi.org/10.3390/biom14060644