RESUMO
MTH1 is a hydrolase responsible for sanitization of oxidized purine nucleoside triphosphates to prevent their incorporation into replicating DNA. Early tool compounds published in the literature inhibited the enzymatic activity of MTH1 and subsequently induced cancer cell death; however recent studies have questioned the reported link between these two events. Therefore, it is important to validate MTH1 as a cancer dependency with high quality chemical probes. Here, we present BAY-707, a substrate-competitive, highly potent and selective inhibitor of MTH1, chemically distinct compared to those previously published. Despite superior cellular target engagement and pharmacokinetic properties, inhibition of MTH1 with BAY-707 resulted in a clear lack of in vitro or in vivo anticancer efficacy either in mono- or in combination therapies. Therefore, we conclude that MTH1 is dispensable for cancer cell survival.
Assuntos
Enzimas Reparadoras do DNA/metabolismo , Sistemas de Liberação de Medicamentos , Morfolinas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CACO-2 , Células Cultivadas , Enzimas Reparadoras do DNA/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Células HeLa , Hepatócitos/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Morfolinas/química , Neoplasias/fisiopatologia , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/farmacologia , RatosRESUMO
Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation. In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.