RESUMEN
We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1ß, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.
RESUMEN
Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.
RESUMEN
We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.
RESUMEN
We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2-{8-fluoro-5-[(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-7-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10.
Asunto(s)
Antineoplásicos/farmacología , Carbolinas/farmacología , Desarrollo de Medicamentos , Proteínas/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Carbolinas/administración & dosificación , Carbolinas/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Estructura Molecular , Proteínas/metabolismo , Relación Estructura-Actividad , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
Asunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , Descubrimiento de Drogas , Fenilalanina/farmacología , Prolina/farmacología , Triptófano/farmacología , Administración Oral , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Carbazoles/administración & dosificación , Carbazoles/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Fenilalanina/administración & dosificación , Fenilalanina/química , Prolina/administración & dosificación , Prolina/química , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Triptófano/administración & dosificación , Triptófano/químicaRESUMEN
We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.
Asunto(s)
Antineoplásicos/farmacología , Carbolinas/farmacología , Desarrollo de Medicamentos , Mieloma Múltiple/dietoterapia , Proteínas/antagonistas & inhibidores , Triazoles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Carbolinas/síntesis química , Carbolinas/química , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Mieloma Múltiple/metabolismo , Proteínas/metabolismo , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
C-terminal Src kinase (CSK) functions as a negative regulator of T cell activation through inhibitory phosphorylation of LCK, so inhibitors of CSK are of interest as potential immuno-oncology agents. Screening of an internal kinase inhibitor collection identified pyridazinone lead 1, and a series of modifications led to optimized compound 13. Compound 13 showed potent activity in biochemical and cellular assays in vitro and demonstrated the ability to increase T cell proliferation induced by T cell receptor signaling. Compound 13 gave extended exposure in mice upon oral dosing and produced a functional response (decrease in LCK phosphorylation) in mouse spleens at 6 h post dose.
RESUMEN
This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.
Asunto(s)
Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Naftalenosulfonatos/química , Naftalenosulfonatos/farmacología , Administración Oral , Antagonistas de Receptores Androgénicos/farmacocinética , Animales , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/farmacocinética , Línea Celular Tumoral , Humanos , Modelos Moleculares , Naftalenosulfonatos/administración & dosificación , Naftalenosulfonatos/farmacocinética , Ratas , Receptores Androgénicos/metabolismo , Relación Estructura-ActividadRESUMEN
Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.
RESUMEN
This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Benzodiazepinonas/administración & dosificación , Benzodiazepinonas/farmacología , Receptores Notch/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Benzodiazepinonas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Receptores Notch/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of 5-((4-aminopiperidin-1-yl)methyl)-pyrrolo[2,1-f][1,2,4]triazin-4-amines with small aniline substituents at the C4 position were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. Compound 8l exhibited promising oral efficacy in both EGFR and HER2-driven human tumor xenograft models.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Receptores ErbB/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Neoplasias/enzimología , Proteínas Tirosina Quinasas/farmacocinética , Proteínas Tirosina Quinasas/farmacología , Pirroles/química , Pirroles/farmacocinética , Pirroles/farmacología , Pirroles/uso terapéutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Triazinas/química , Triazinas/farmacocinética , Triazinas/farmacología , Triazinas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.
Asunto(s)
Antineoplásicos/síntesis química , Carbamatos/síntesis química , Receptores ErbB/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Triazinas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Carbamatos/farmacocinética , Carbamatos/farmacología , Línea Celular Tumoral , Perros , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Macaca fascicularis , Ratones , Trasplante de Neoplasias , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacologíaRESUMEN
A G-Protein-coupled receptor-targeted library of aryloxypropanolamines and aryloxybutanolamines was efficiently executed using a novel, polymer-supported acyclic acetal linker, producing compounds in good yields and purities.
Asunto(s)
Aminas/síntesis química , Diseño de Fármacos , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Aminas/farmacología , Técnicas Químicas Combinatorias , Reactivos de Enlaces Cruzados , Humanos , Polímeros , Propanolaminas , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
PURPOSE: The studies described here are intended to characterize the ability of BMS-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2. EXPERIMENTAL DESIGN: The potency and selectivity of BMS-599626 were assessed in biochemical assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was determined in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunoprecipitation. Antitumor activity of BMS-599626 was evaluated using a number of different xenograft models that represent a spectrum of human tumors with HER1 or HER2 overexpression. RESULTS: BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 micromol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity. CONCLUSIONS: BMS-599626 is a highly selective and potent inhibitor of HER1 and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an additional mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth. The preclinical data support the advancement of BMS-599626 into clinical development for the treatment of cancer.
Asunto(s)
Antineoplásicos/toxicidad , Inhibidores Enzimáticos/toxicidad , Receptores ErbB/antagonistas & inhibidores , Receptor ErbB-2/antagonistas & inhibidores , Anticuerpos Monoclonales/farmacología , Antígenos CD8/inmunología , División Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Dimerización , HumanosRESUMEN
A novel series of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3) inhibitors has been identified. These inhibitors, based on a dibenzazocine core, exhibited picomolar to low nanomolar inhibition of 17beta-HSD3 in cell-free enzymatic as well as in cell-based transcriptional reporter assays.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Azocinas , Inhibidores Enzimáticos , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Fosfatasa Alcalina/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Androstenodiona/metabolismo , Azocinas/síntesis química , Azocinas/química , Azocinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Testosterona/biosíntesisRESUMEN
A 3D quantitative structure-activity relationship study for inhibition of calcium-sensing receptor in the aryloxypropanolamine series predicted that these molecules adopt a U-shaped conformation with pi-stacking between the two aromatic rings. This hypothesis led to the discovery of novel 1-arylmethyl pyrrolidin-2-yl ethanol amines capable of antagonizing the calcium-sensing receptor with potency comparable to that of NPS-2143.
Asunto(s)
Receptores Sensibles al Calcio/antagonistas & inhibidores , Etanolaminas/síntesis química , Etanolaminas/química , Etanolaminas/farmacología , Humanos , Modelos Moleculares , Conformación Molecular , Osteoporosis/tratamiento farmacológico , Conformación Proteica , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores Sensibles al Calcio/química , Relación Estructura-ActividadRESUMEN
A comparative molecular similarity index analysis (CoMSiA) has been performed for cytochrome P450 2D6 inhibition on a series of aryloxypropanolamines to determine the factors contributing to this activity. The model is in agreement with a CYP2D6 homology model constructed on the basis of the mammalian CYP2C5 crystal structure. The energy minimized conformations were generated using the systematic search methodology in Sybyl 6.7. The model not only elucidated the relationship between structure and biological activity but, more importantly, provided useful strategies to modulate CYP2D6 affinity in the aryloxypropanolamine series.
Asunto(s)
Inhibidores del Citocromo P-450 CYP2D6 , Propanolaminas/química , Relación Estructura-Actividad Cuantitativa , Animales , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Propanolaminas/farmacología , Especificidad por SustratoRESUMEN
Benzylic and allylic organozinc and Grignard reagents have been added to resin-bound imines to provide alpha-branched secondary amines. Many functional groups, including electrophilic groups, were compatible with this methodology. Three modules--a resin-bound primary amine, an aromatic aldehyde, and the organometallic--were independently varied to produce a combinatorial library of alpha-branched secondary amines designed as beta-3 adrenergic receptor agonists.