RESUMO
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.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Camundongos , Animais , Nucleosídeos , 5'-Nucleotidase , Neoplasias/tratamento farmacológico , Modelos Animais de Doenças , Monofosfato de AdenosinaRESUMO
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.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Quinolinas/química , Semicarbazidas/química , Tioureia/análogos & derivados , Animais , Cães , Feminino , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Quinase I-kappa B/metabolismo , Macaca mulatta , Masculino , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Semicarbazidas/síntese química , Semicarbazidas/farmacocinética , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química , Tioureia/farmacocinéticaRESUMO
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.
Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Semicarbazidas/química , Animais , Cães , Feminino , Ensaios de Triagem em Larga Escala , Quinase I-kappa B/metabolismo , Masculino , Microssomos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/química , Ratos , Semicarbazidas/síntese química , Semicarbazidas/farmacocinética , Relação Estrutura-AtividadeRESUMO
A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.
Assuntos
Anti-Inflamatórios/síntese química , Pirazóis/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Trifosfato de Adenosina/química , Administração Oral , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Cães , Feminino , Haplorrinos , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-1/biossíntese , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Modelos Moleculares , Pirazóis/química , Pirazóis/farmacologia , Ratos , Ratos Endogâmicos Lew , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/químicaRESUMO
Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2(+) cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors.
Assuntos
Antineoplásicos/administração & dosagem , Benzenoacetamidas/farmacologia , Inibidores Enzimáticos/administração & dosagem , Glutaminase/antagonistas & inibidores , Neoplasia de Células Basais/tratamento farmacológico , Tiadiazóis/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/uso terapêutico , Benzenoacetamidas/uso terapêutico , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Neoplasias Mamárias Experimentais , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Neoplasia de Células Basais/patologia , Sulfetos/administração & dosagem , Sulfetos/uso terapêutico , Tiadiazóis/administração & dosagem , Tiadiazóis/uso terapêutico , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.