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Computational and Biological Investigations on Abl1 Tyrosine Kinase: A Review
Masilamani Elizabeth Sobhia1, G Siva Kumar1, Antara Mallick1
1Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, India.
Abstract:
Abl1 tyrosine kinase is a validated target for the treatment of chronic myeloid leukemia. It is a form of cancer that is difficult to treat and much research is being done to identify new molecular entities and to tackle drug resistance issues. In recent years, drug resistance of Abl1 tyrosine kinase has become a major healthcare concern. Second and third-generation TKI reported better responses against the resistant forms; still they had no impact on long-term survival prolongation. New compounds derived from natural products and organic small molecule inhibitors can lay the foundation for better clinical therapies in the future. Computational methods, experimental and biological studies can help us understand the mechanism of drug resistance and identify novel molecule inhibitors. ADMET parameters analysis of reported drugs and novel small molecule inhibitors can also provide valuable insights. In this review, available therapies, point mutations, structure-activity relationship and ADMET parameters of reported series of Abl1 tyrosine kinase inhibitors and drugs are summarised. We summarise in detail recent computational and molecular biology studies that focus on designing drug molecules, investigation of natural product compounds and organic new chemical entities. Current ongoing research suggests that selective targeting of Abl1 tyrosine kinase at the molecular level to combat drug resistance in chronic myeloid leukemia is promising.
Insights
Drug resistance in chronic myeloid leukemia (CML) is a major concern. New molecular entities and computational methods offer promising strategies for developing effective Abl1 tyrosine kinase inhibitors to overcome resistance and improve long-term survival.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Abl1 tyrosine kinase is a validated target for chronic myeloid leukemia (CML).
- Drug resistance to existing therapies, including TKIs, is a significant clinical challenge in CML.
- Limited long-term survival benefits are observed with current second and third-generation TKIs against resistant CML forms.
Purpose of the Study:
- To review current therapies for CML targeting Abl1 tyrosine kinase.
- To explore mechanisms of drug resistance, including point mutations.
- To summarize novel therapeutic strategies, including natural products and small molecule inhibitors, for overcoming Abl1 resistance.
Main Methods:
- Review of available therapies, point mutations, and structure-activity relationships of Abl1 inhibitors.
- Summary of computational, experimental, and biological studies on drug resistance mechanisms.
- Analysis of ADMET parameters for existing drugs and novel inhibitors.
Main Results:
- Second and third-generation TKIs show improved responses but do not significantly prolong long-term survival in resistant CML.
- Natural product derivatives and organic small molecules represent potential avenues for new CML therapies.
- Computational and molecular biology studies are crucial for understanding resistance and designing new inhibitors.
Conclusions:
- Selective targeting of Abl1 tyrosine kinase at the molecular level is a promising strategy to combat drug resistance in CML.
- Further research into novel compounds and resistance mechanisms is essential for advancing CML treatment.
- Integrating computational and experimental approaches can accelerate the discovery of effective CML therapies.
