RESUMO
Due to rising costs and the difficulty to identify new targets, drug repurposing appears as a viable strategy for the development of new anti-cancer treatments. Although the interest of disulfiram (DSF), an anti-alcohol drug, to treat cancer was reported for many years, it is only very recently that one anticancer mechanism-of-action was highlighted. This would involve the inhibition of the p97 segregase adaptor NPL4, which is essential for the turnover of proteins involved in multiple regulatory and stress-response intracellular pathways. However, recently DSF was also reported as one of the first phosphoglycerate dehydrogenase (PHGDH) inhibitors, a tetrameric enzyme catalyzing the initial step of the serine synthetic pathway that is highly expressed in numerous cancer types. Here, we investigated the structure-activity relationships (SAR) of PHGDH inhibition by disulfiram analogues as well as the mechanism of action of DSF on PHGDH via enzymatic and cell-based evaluation, mass spectrometric and mutagenesis experiments.
Assuntos
Antineoplásicos/farmacologia , Cisteína/metabolismo , Dissulfiram/farmacologia , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Multimerização Proteica/efeitos dos fármacos , Dissuasores de Álcool/farmacologia , Dissulfiram/análogos & derivados , Reposicionamento de Medicamentos , Humanos , Oxirredução , Relação Estrutura-AtividadeRESUMO
Docking studies of 4-phenylthiazolinethione on human IDO1 suggest complexation of the heme iron by the exocyclic sulfur atom further reinforced by hydrophobic interactions of the phenyl ring within pocket A of the enzyme. On this basis, chemical modifications were proposed to increase inhibition activity. Synthetic routes had to be adapted and optimized to yield the desired substituted 4- and 5-arylthiazolinethiones. Their biological evaluation shows that 5-aryl regioisomers are systematically less potent than the corresponding 4-aryl analogs. Substitution on the phenyl ring does not significantly increase inhibition potency, except for 4-Br and 4-Cl derivatives.