Discovery of selective LATS inhibitors via scaffold hopping: enhancing drug-likeness and kinase selectivity for potential applications in regenerative medicine

Due to its essential roles in cell proliferation and apoptosis, the precise regulation of the Hippo pathway through LATS presents a viable biological target for developing new drugs for cancer and regenerative diseases. However, currently available probes for selective and highly drug-like inhibitio...

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Bibliographic Details
Published in:MedChemComm 2024-09, Vol.15 (12), p.4080-4089
Main Authors: Issabayeva, Guldana, Kang, On-Yu, Choi, Seong Yun, Hyun, Ji Young, Park, Seong Jun, Jeung, Hei-Cheul, Lim, Hwan Jung
Format: Article
Language:English
Subjects:
Apoptosis
Biological activity
Cell proliferation
Chemistry
Drug discovery
Enzyme inhibitors
Kinases
Pharmacokinetics
Regenerative medicine
Scaffolds
Selectivity
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Summary:Due to its essential roles in cell proliferation and apoptosis, the precise regulation of the Hippo pathway through LATS presents a viable biological target for developing new drugs for cancer and regenerative diseases. However, currently available probes for selective and highly drug-like inhibition of LATS require further improvement in terms of both activity, selectivity and drug-like properties. Through scaffold hopping aided by docking studies and AI-assisted prediction of metabolic stabilities, we successfully identified an advanced LATS inhibitor demonstrating potent kinase activity, exceptional selectivity against other kinases, and superior oral pharmacokinetic profiles.
ISSN:2632-8682
2040-2503
2632-8682
2040-2511
DOI:10.1039/d4md00492b