RESUMEN
Restoration of p53 function through the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer. Here, we present kinetic, thermodynamic, and structural rationale for the remarkable potency of a new class of MDM2 inhibitors, the piperidinones. While these compounds bind to the same site as previously reported for small molecule inhibitors, such as the Nutlins, data presented here demonstrate that the piperidinones also engage the N-terminal region (residues 10-16) of human MDM2, in particular, Val14 and Thr16. This portion of MDM2 is unstructured in both the apo form of the protein and in MDM2 complexes with p53 or Nutlin, but adopts a novel ß-strand structure when complexed with the piperidinones. The ordering of the N-terminus upon binding of the piperidinones extends the current model of MDM2-p53 interaction and provides a new route to rational design of superior inhibitors.
Asunto(s)
Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Cristalografía por Rayos X , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-Actividad , TermodinámicaRESUMEN
A novel series of benzenesulfonanilide derivatives of 11ß-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11ß-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Anilidas/química , Compuestos de Anilina/química , Inhibidores Enzimáticos/química , Piperazinas/química , Sulfonamidas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/farmacología , Anilidas/síntesis química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Conformación Molecular , Piperazina , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , TransfecciónRESUMEN
Human murine double minute 2 (MDM2) is a negative regulator of p53, which plays an important role in cell cycle and apoptosis. We report several optimizations to the synthesis of the chromenotriazolopyrimidine series of MDM2-p53 protein-protein interaction inhibitors. Additionally, the in vitro and in vivo stability, pharmacokinetic properties and solubility were improved through N-substitution.
Asunto(s)
Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirimidinas/síntesis química , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Estabilidad de Medicamentos , Humanos , Bombas de Infusión , Concentración 50 Inhibidora , Estructura Molecular , Pirimidinas/farmacocinética , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/química , Inhibidores Enzimáticos/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Ramoplanin is a potent lipoglycodepsipeptide antibiotic that is active against a wide range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). It acts as an inhibitor of peptidoglycan (PG) biosynthesis that disrupts glycan chain polymerization by binding and sequestering Lipid II, a PG precursor. Herein, we report the functional antimicrobial activity (MIC, S. aureus) and fundamental biochemical assessments against a peptidoglycan glycosyltransferase (Escherichia coli PBP1b) of a set of key alanine scan analogues of ramoplanin that provide insight into the importance and role of each of its individual amino acid residues.
Asunto(s)
Antibacterianos/química , Depsipéptidos/química , Antibacterianos/farmacología , Depsipéptidos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/enzimología , Bacterias Grampositivas/efectos de los fármacos , Peptidoglicano Glicosiltransferasa/antagonistas & inhibidores , Peptidoglicano Glicosiltransferasa/metabolismoRESUMEN
Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina/metabolismo , Piperidinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Benzamidas/farmacología , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Hepatocitos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Microsomas/metabolismo , Modelos Químicos , Estructura Molecular , Solubilidad , Relación Estructura-ActividadRESUMEN
Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Animales , Benzamidas/farmacología , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Macaca fascicularis , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 (15) emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to 1. Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.
Asunto(s)
Mifepristona/análogos & derivados , Mifepristona/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Receptores Androgénicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/antagonistas & inhibidores , Receptores de Progesterona/metabolismoRESUMEN
Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Fenilacetatos/química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Estabilidad de Medicamentos , Femenino , Humanos , Enlace de Hidrógeno , Ratones Desnudos , Mieloma Múltiple/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.
Asunto(s)
Descubrimiento de Drogas , Antagonistas de Hormonas/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Receptores de Glucocorticoides/antagonistas & inhibidores , Animales , Femenino , Antagonistas de Hormonas/química , Antagonistas de Hormonas/farmacocinética , Humanos , Ratones , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Ratas , Porcinos , Porcinos Enanos , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The synthesis and biological test results of a series of enkephalin analogues incorporating the lanthionine modification are presented. The syntheses of four monosulfide-bridged analogues of enkephalins, Tyr-c[D-Ala(L)-Gly-Phe-D-Ala(L)]-OH (1a), Tyr-c[D-Val(L)-Gly-Phe-D-Ala(L)]-OH (1b), Tyr-c[D-Ala(L)-Gly-Phe-Ala(L)]-OH (1c), and Tyr-c[D-Val(L)-Gly-Phe-Ala(L)]-OH (1d), where Ala(L) and Val(L) denote the lanthionine amino acid ends linked by a monosulfide bridge to form the lanthionine structure, were successfully carried out via preparation of the linear peptide on solid support and cyclization in solution. In vitro binding assays against mu-, delta-, and kappa-opioid receptors and in vitro tests using GPI and MVD assays revealed that the dimethyl lanthionine analogues 1b and 1d, denoted as D-Val(L) in position 2, show substantial selectivity toward the delta-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as D-Ala(L) in position 2, bind to both mu- and delta-opioid receptors. The in vivo thermal escape assay by intrathecal administration showed that the analogues 1b and 1d are among the most potent ligands at producing antinociception through the delta-opioid receptor. The picomolar potencies of analogues 1a and 1c in the intrathecal (it.) assay strongly indicate that mu- and delta-opioid receptors interact synergistically to modulate the antinociceptive responses.
Asunto(s)
Alanina/análogos & derivados , Alanina/síntesis química , Encefalinas/síntesis química , Receptores Opioides delta/metabolismo , Alanina/química , Alanina/farmacología , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacología , Animales , Células CHO , Cricetinae , Encefalinas/química , Encefalinas/farmacología , Reacción de Fuga/efectos de los fármacos , Humanos , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Inyecciones Espinales , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Sulfuros , Porcinos , Conducto Deferente/efectos de los fármacos , Conducto Deferente/fisiologíaRESUMEN
We recently reported the discovery of AMG 232 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 protein-protein interaction. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer. This article provides an overview of its discovery from the de novo design of the piperidinone series to the structure-activity studies leading to the identification of 1. In addition, this article also describes the preclinical pharmacology and pharmacokinetics of 1, along with its drug metabolism and safety assessment.
Asunto(s)
Acetatos/química , Antineoplásicos/química , Piperidonas/química , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Acetatos/efectos adversos , Acetatos/farmacología , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Sitios de Unión , Humanos , Modelos Moleculares , Piperidonas/efectos adversos , Piperidonas/farmacología , Unión Proteica , Conformación Proteica , Relación Estructura-ActividadRESUMEN
In this letter, we reported the design and synthesis of three potent, selective, and orally bioavailable 11ß-HSD1 inhibitors labeled with (14)C: AMG 456 (1), AM-6949 (2), and AM-7715 (3). We evaluated the covalent protein binding of the labeled inhibitors in human liver microsomes in vitro and assessed their potential bioactivation risk in humans. We then studied the in vitro mechanism of 2 in human hepatocytes and the formation of reactive intermediates. Our study results suggest that 1 and 3 have low potential for metabolic bioactivation in humans, while 2 has relatively high risk.
RESUMEN
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Descubrimiento de Drogas , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Antineoplásicos/química , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
Asunto(s)
Acetatos/síntesis química , Acetatos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Morfolinas/síntesis química , Morfolinas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/química , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/química , Animales , Línea Celular Tumoral , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Indicadores y Reactivos , Ratones , Modelos Moleculares , Conformación Molecular , Morfolinas/farmacocinética , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.
RESUMEN
We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
Asunto(s)
Acetatos/farmacología , Antineoplásicos/farmacología , Ácidos Carboxílicos/farmacología , Proliferación Celular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Piperidonas/farmacología , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Acetatos/química , Animales , Neoplasias Óseas/tratamiento farmacológico , Ácidos Carboxílicos/química , Células Cultivadas , Cristalografía por Rayos X , Diseño de Fármacos , Femenino , Humanos , Enlace de Hidrógeno , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Osteosarcoma/tratamiento farmacológico , Piperidonas/química , Unión Proteica , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Asunto(s)
Acetatos/farmacología , Antineoplásicos/farmacología , Piperidonas/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Acetatos/química , Administración Oral , Antineoplásicos/química , Disponibilidad Biológica , Cristalografía por Rayos X , Descubrimiento de Drogas , Humanos , Piperidonas/química , Conformación ProteicaRESUMEN
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 µM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 µM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Dicroismo Circular , Cristalografía , Cristalografía por Rayos X , Diseño de Fármacos , Femenino , Humanos , Indicadores y Reactivos , Ratones , Ratones Desnudos , Modelos Moleculares , Morfolinas/síntesis química , Morfolinas/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.