RESUMEN
Bicycles are constrained bicyclic peptides formed through reaction of three cysteine residues within a linear sequence with a trivalent, symmetrical small molecule scaffold. Bicycles with high binding affinities to therapeutically important targets can be discovered using screening technologies such as phage display. Increasing the chemical diversity of Bicycles should improve the probability of finding hits to new targets and can be achieved by expanding the toolbox of Bicycle forming chemistries. Gold(III) S-arylation has recently been described as a method for the efficient bioconjugation of cysteine residues under conditions compatible with phage display. Herein, we explore the scope and generality of this methodology for Bicycle construction through the synthesis and evaluation of four novel tris-Gold complexes. These new scaffolds were systematically reacted with a variety of peptide sequences, varying in amino acid loop lengths. All four scaffolds proved to be capable and selective reactive partners for each peptide sequence and afforded the desired Bicycle products in 13-48% isolated yield. This work exemplifies Gold-mediated arylation as a general approach for construction of novel, highly constrained Bicycles.
Asunto(s)
Cisteína , Oro , Secuencia de Aminoácidos , Ciclismo , Cisteína/química , Oro/química , Biblioteca de Péptidos , Péptidos/químicaRESUMEN
BACKGROUND: CD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent CD137 agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide (Bicycle®) technology. Nectin-4 is overexpressed in multiple human cancers that may benefit from CD137 agonism. To this end, we have developed BT7480, a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™). METHODS: Nectin-4 and CD137 co-expression analyses in primary human cancer samples was performed. Chemical conjugation of two CD137 Bicycles to a Nectin-4 Bicycle led to BT7480, which was then evaluated using a suite of in vitro and in vivo assays to characterize its pharmacology and mechanism of action. RESULTS: Transcriptional profiling revealed that Nectin-4 and CD137 were co-expressed in a variety of human cancers with high unmet need and spatial proteomic imaging found CD137-expressing immune cells were deeply penetrant within the tumor near Nectin-4-expressing cancer cells. BT7480 binds potently, specifically, and simultaneously to Nectin-4 and CD137. In co-cultures of human peripheral blood mononuclear cells and tumor cells, this co-ligation causes robust Nectin-4-dependent CD137 agonism that is more potent than an anti-CD137 antibody agonist. Treatment of immunocompetent mice bearing Nectin-4-expressing tumors with BT7480 elicited a profound reprogramming of the tumor immune microenvironment including an early and rapid myeloid cell activation that precedes T cell infiltration and upregulation of cytotoxicity-related genes. BT7480 induces complete tumor regressions and resistance to tumor re-challenge. Importantly, antitumor activity is not dependent on continuous high drug levels in the plasma since a once weekly dosing cycle provides maximum antitumor activity despite minimal drug remaining in the plasma after day 2. BT7480 appears well tolerated in both rats and non-human primates at doses far greater than those expected to be clinically relevant, including absence of the hepatic toxicity observed with non-targeted CD137 agonists. CONCLUSION: BT7480 is a highly potent Nectin-4-dependent CD137 agonist that produces complete regressions and antitumor immunity with only intermittent drug exposure in syngeneic mouse tumor models and is well tolerated in preclinical safety species. This work supports the clinical investigation of BT7480 for the treatment of cancer in humans.
Asunto(s)
Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Animales , Humanos , Ratones , Neoplasias/inmunología , Ratas , Microambiente TumoralRESUMEN
Drugs that block voltage-gated sodium channels (NaVs) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved NaV blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.
RESUMEN
ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.
Asunto(s)
MAP Quinasa Quinasa Quinasa 5/antagonistas & inhibidores , MAP Quinasa Quinasa Quinasa 5/química , Estaurosporina/química , Sitios de Unión , Enfermedades Cardiovasculares/tratamiento farmacológico , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Ligandos , MAP Quinasa Quinasa Quinasa 5/genética , MAP Quinasa Quinasa Quinasa 5/metabolismo , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Células Sf9 , Transducción de SeñalAsunto(s)
Diabetes Mellitus/tratamiento farmacológico , Descubrimiento de Drogas , Glucoquinasa/metabolismo , Quinasas Janus/antagonistas & inhibidores , Malaria/tratamiento farmacológico , Receptores de Glucagón/agonistas , Animales , Antimaláricos/química , Antimaláricos/farmacología , Benzamidas/química , Benzamidas/farmacología , Descubrimiento de Drogas/métodos , Receptor del Péptido 1 Similar al Glucagón , Glucoquinasa/química , Humanos , Plasmodium/efectos de los fármacosAsunto(s)
Investigación Biomédica/tendencias , Industria Farmacéutica/tendencias , Investigación Biomédica/métodos , Diseño de Fármacos , Industria Farmacéutica/métodos , Epigénesis Genética , Mapeo de Interacción de Proteínas , Receptor Muscarínico M2/antagonistas & inhibidores , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Canales Catiónicos TRPV/antagonistas & inhibidoresAsunto(s)
Descubrimiento de Drogas/métodos , Animales , Asma/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/metabolismo , Humanos , Iminoazúcares/uso terapéutico , Enfermedades del Sistema Inmune/tratamiento farmacológico , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismoRESUMEN
A pharmacophore model was built, based on known CGRP receptor antagonists, and this was used to aid the identification of novel leads. Analogues were designed, modelled and synthesised which incorporated alternative 'LHS' fragments linked via either an amide or urea to a privileged 'RHS' fragment commonly found in CGRP receptor antagonists. As a result a novel series of oxadiazole CGRP receptor antagonists has been identified and the subsequent optimisation to enhance both potency and bioavailability is presented.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Diseño de Fármacos , Trastornos Migrañosos/tratamiento farmacológico , Oxadiazoles/síntesis química , Oxadiazoles/uso terapéutico , Administración Oral , Animales , Modelos Moleculares , Estructura Molecular , Oxadiazoles/química , RatasRESUMEN
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Asunto(s)
Antidepresivos Tricíclicos/síntesis química , Encéfalo/efectos de los fármacos , Química Farmacéutica/métodos , Receptores de Serotonina/química , Antagonistas de la Serotonina/síntesis química , Animales , Antidepresivos Tricíclicos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/química , Humanos , Enlace de Hidrógeno , Microsomas/efectos de los fármacos , Modelos Químicos , Conformación Molecular , Isoformas de Proteínas , Ratas , Antagonistas de la Serotonina/farmacologíaRESUMEN
The pursuit of MCH R1 antagonists for the treatment of obesity has become an active area of research for many pharmaceutical companies. The evidence supporting the use of MCH R1 antagonists for the treatment of obesity is ample, and the recent demonstration of MCH R1 antagonists' efficacy in animal models of obesity has served to augment earlier studies involving MCH peptide and transgenic animals. We report herein our search for MCH R1 antagonists from the discovery of a biphenyl amide by high throughput screening, through the optimization of the biphenyl amide to a series of constrained aryl-substituted thienopyrimidinones, and extending the application of the thienopyrimidinone substructure to other series of MCH R1 antagonists. Importantly, these MCH R1 antagonists have demonstrated efficacy in animal models of obesity through once-daily oral administration at low doses.
Asunto(s)
Amidas/química , Amidas/farmacología , Compuestos de Bifenilo/química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de la Hormona Hipofisaria/metabolismo , Amidas/farmacocinética , Animales , Humanos , Modelos Moleculares , Quinolinas/química , Receptores de la Hormona Hipofisaria/química , Relación Estructura-ActividadRESUMEN
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Asunto(s)
Amidas/química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bovinos , Biología Computacional , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Azufre/químicaRESUMEN
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.