Enhancing the affinity of novel GLS1 allosteric inhibitors by targeting key residue Lys320.
Future Med Chem
; 15(15): 1393-1414, 2023 Aug.
Article
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| MEDLINE
| ID: mdl-37610850
ABSTRACT
Aim:
A series of novel GLS1 irreversible allosteric inhibitors targeting Lys320 might have robust enzyme inhibitory activity and potent antitumor activity. Materials &methods:
Novel GLS1 allosteric inhibitors targeting Lys320 were synthesized and their anticancer activity was assessed. Moreover, GLS1 protein was used as a model system to analyze the reactivity of these electrophilic groups in GLS1 irreversible allosteric inhibitors with other amino acids, including tyrosine, histidine, serine and threonine, using biochemical and biophysical assays.Results:
AC16 exhibited robust GLS1 inhibitory activity, antiproliferative effect in vitro, good plasma stability and potential covalent addition with GLS1 K320.Conclusion:
This study opens a novel avenue for the design of robust irreversible GLS1 inhibitors targeting the allosteric site K320.
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Future Med Chem
Año:
2023
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Article