RESUMEN
CD73 (ecto-5'-nucleotidase) has emerged as an attractive target for cancer immunotherapy of many cancers. CD73 catalyzes the hydrolysis of adenosine monophosphate (AMP) into highly immunosuppressive adenosine that plays a critical role in tumor progression. Herein, we report our efforts in developing orally bioavailable and highly potent small-molecule CD73 inhibitors from the reported hit molecule 2 to lead molecule 20 and then finally to compound 49. Compound 49 was able to reverse AMP-mediated suppression of CD8+ T cells and completely inhibited CD73 activity in serum samples from various cancer patients. In preclinical in vivo studies, orally administered 49 showed a robust dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship that correlated with efficacy. Compound 49 also demonstrated the expected immune-mediated antitumor mechanism of action and was efficacious upon oral administration not only as a single agent but also in combination with either chemotherapeutics or checkpoint inhibitor in the mouse tumor model.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Ratones , Animales , Nucleósidos , 5'-Nucleotidasa , Neoplasias/tratamiento farmacológico , Modelos Animales de Enfermedad , Adenosina MonofosfatoRESUMEN
Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26pmol/mg protein.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridonas/química , Agammaglobulinemia Tirosina Quinasa , Glutatión/química , Espectroscopía de Resonancia Magnética , Microsomas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Piridonas/metabolismo , Espectrometría de Masas en TándemRESUMEN
A new synthesis of di- and trisubstituted pyrroles was achieved by treating in situ generated vinylogous diazoesters and readily available nitriles with a catalytic amount of silver(I) antimony hexafluoride at room temperature. This method showcased the potential of utilizing silver(I) carbenoids in preparing heterocyclic compounds.
Asunto(s)
Nitrilos/química , Pirroles/síntesis química , Plata/química , Catálisis , Técnicas Químicas Combinatorias , Reacción de Cicloadición , Estructura Molecular , Pirroles/químicaRESUMEN
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Asunto(s)
Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , RatasRESUMEN
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Quinolinas/química , Semicarbacidas/química , Tiourea/análogos & derivados , Animales , Perros , Femenino , Hepatocitos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Quinasa I-kappa B/metabolismo , Macaca mulatta , Masculino , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Semicarbacidas/síntesis química , Semicarbacidas/farmacocinética , Relación Estructura-Actividad , Tiourea/síntesis química , Tiourea/química , Tiourea/farmacocinéticaRESUMEN
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.