Advances in the discovery of activin receptor-like kinase 5 (ALK5) inhibitors

[Display omitted] Activin receptor‑like kinase-5 (ALK5) is an outstanding member of the transforming growth factor-β (TGF-β) family. (TGF-β) signaling pathway integrates pleiotropic proteins that regulate various cellular processes such as growth, proliferation, and differentiation. Dysregulation wi...

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Bibliographic Details
Published in:Bioorganic chemistry 2024-06, Vol.147, p.107332-107332, Article 107332
Main Authors: Mansour, Mai A., Hassan, Ghaneya S., Serya, Rabah A.T., Jaballah, Maiy Y., Abouzid, Khaled A.M.
Format: Article
Language:English
Subjects:
ALK5
ALK5 inhibitors
Animals
Binding interactions
Drug Discovery
Humans
Molecular Structure
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Receptor, Transforming Growth Factor-beta Type I - antagonists & inhibitors
Receptor, Transforming Growth Factor-beta Type I - metabolism
Structure-Activity Relationship
TGF-β
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Summary:[Display omitted] Activin receptor‑like kinase-5 (ALK5) is an outstanding member of the transforming growth factor-β (TGF-β) family. (TGF-β) signaling pathway integrates pleiotropic proteins that regulate various cellular processes such as growth, proliferation, and differentiation. Dysregulation within the signaling pathway can cause variety of diseases, such as fibrosis, cardiovascular disease, and especially cancer, rendering ALK5 a potential drug target. Hence, various small molecules have been designed and synthesized as potent ALK5 inhibitors. In this review, we shed light on the current ATP-competitive inhibitors of ALK5 through diverse heterocyclic based scaffolds that are in clinical or pre-clinical phases of development. Moreover, we focused on the binding interactions of the compounds to the ATP binding site and the structure–activity relationship (SAR) of each scaffold, revealing new scopes for designing novel candidates with enhanced selectivity and metabolic profiles.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2024.107332