RESUMEN
The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/ß) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.
Asunto(s)
Descubrimiento de Drogas , Receptores Nucleares Huérfanos/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Células HEK293 , Células Hep G2 , Humanos , Ligandos , Receptores X del Hígado , Masculino , Ratones , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , BencenosulfonamidasRESUMEN
Two classes of ACK1 inhibitors, 4,5,6-trisubstituted furo[2,3-d]pyrimidin4-amines and 4,5,6-trisubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amines, were discovered and evaluated as ACK1 inhibitors. Further structural refinement led to the identification of potent and selective dithiolane inhibitor 37.
Asunto(s)
Furanos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Relación Dosis-Respuesta a Droga , Furanos/síntesis química , Furanos/química , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Structural modification of a series of dual LXRα/ß agonists led to the identification of a new class of LXRß partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRß with a reversed orientation compared to 1.
Asunto(s)
Receptores Nucleares Huérfanos/agonistas , Isoformas de Proteínas/agonistas , Pirroles/síntesis química , Sitios de Unión , Células CACO-2 , Cristalografía por Rayos X , Genes Reporteros , Células HEK293 , Humanos , Receptores X del Hígado , Receptores Nucleares Huérfanos/química , Unión Proteica , Isoformas de Proteínas/química , Pirroles/farmacología , Relación Estructura-Actividad , TransfecciónRESUMEN
A comprehensive understanding of structure-reactivity relationships is critical to the design and optimization of cysteine-targeted covalent inhibitors. Herein, we report glutathione (GSH) reaction rates for N-phenyl acrylamides with varied substitutions at the α- and ß-positions of the acrylamide moiety. We find that the GSH reaction rates can generally be understood in terms of the electron donating or withdrawing ability of the substituent. When installed at the ß-position, aminomethyl substituents with amine pKa's > 7 accelerate, while those with pKa's < 7 slow the rate of GSH addition at pH 7.4, relative to a hydrogen substituent. Although a computational model was able to only approximately capture experimental reactivity trends, our calculations do not support a frequently invoked mechanism of concerted amine/thiol proton transfer and C-S bond formation and instead suggest that protonated aminomethyl functions as an electron-withdrawing group to reduce the barrier for thiolate addition to the acrylamide.
Asunto(s)
Acrilamidas/síntesis química , Glutatión/química , Acrilamidas/química , Aminas/química , Cisteína/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRASG12C to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRASG12C inhibitor currently in phase I clinical trials (NCT03600883).
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirimidinonas/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Ensayos Clínicos como Asunto , Perros , Descubrimiento de Drogas , Humanos , Isomerismo , Células de Riñón Canino Madin Darby , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Piperazinas/química , Piperazinas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Eukaryotic mRNAs are appended at the 5' end, with the 7-methylguanosine cap linked by a 5'-5'-triphosphate bridge to the first transcribed nucleoside (m7GpppX). Initiation of cap-dependent translation of mRNA requires direct interaction between the cap structure and the eukaryotic translation initiation factor eIF4E. Biophysical studies of the association between eIF4E and various cap analogs have demonstrated that m(7)GTP binds to the protein ca. -5.0 kcal/mol more favorably than unmethylated GTP. In this work, a thermodynamic analysis of the binding process between eIF4E and several cap analogs has been conducted using Monte Carlo (MC) simulations in conjunction with free energy perturbation (FEP) calculations. To address the role of the 7-methyl group in the eIF4E/m7GpppX cap interaction, binding free energies have been computed for m(7)GTP, GTP, protonated GTP at N(7), the 7-methyldeazaguanosine 5'-triphosphate (m(7)DTP), and 7-deazaguanosine 5'-triphosphate (DTP) cap analogs. The MC/FEP simulations for the GTP-->m(7)DTP transformation demonstrate that half of the binding free energy gain of m(7)GTP with respect to GTP can be attributed to favorable van der Waals interactions with Trp166 and reduced desolvation penalty due to the N(7) methyl group. The methyl group both eliminates the desolvation penalty of the N(7) atom upon binding and creates a larger cavity within the solvent that further facilitates the desolvation step. Analysis of the pair m(7)GTP-m(7)DTP suggests that the remaining gain in affinity is related to the positive charge created on the guanine moiety due to the N(7) methylation. The charge provides favorable cation-pi interactions with Trp56 and Trp102 and decreases the negative molecular charge, which helps the transfer from the solvent, a more polar environment, to the protein.
Asunto(s)
Factor 4E Eucariótico de Iniciación/química , Caperuzas de ARN/química , Termodinámica , Biología Computacional , Simulación por Computador , Cristalografía por Rayos X , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Enlace de Hidrógeno , Metilación , Modelos Moleculares , Método de Montecarlo , Unión Proteica , Análogos de Caperuza de ARN/química , Caperuzas de ARN/metabolismoRESUMEN
KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3-5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRASG12C identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRASG12C with submicromolar inhibition of downstream signaling in a KRASG12C-specific manner.
RESUMEN
A new series of pyrazolo[3,4-d]pyrimidine-3,6-diamines was designed and synthesized as potent and selective inhibitors of the nonreceptor tyrosine kinase, ACK1. These compounds arose from efforts to rigidify an earlier series of N-aryl pyrimidine-5-carboxamides. The synthesis and structure-activity relationships of this new series of inhibitors are reported. The most promising compounds were also profiled for their pharmacokinetic properties.
Asunto(s)
Diaminas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/química , Pirimidinas/química , Animales , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Masculino , Modelos Químicos , Conformación Molecular , Proteínas Tirosina Quinasas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The eukaryotic initiation factor 4E (eIF4E) plays a central role in the initiation of gene translation and subsequent protein synthesis by binding the 5' terminal mRNA cap structure. We designed and synthesized a series of novel compounds that display potent binding affinity against eIF4E despite their lack of a ribose moiety, phosphate, and positive charge as present in m7-GMP. The biochemical activity of compound 33 is 95 nM for eIF4E in an SPA binding assay. More importantly, the compound has an IC(50) of 2.5 µM for inhibiting cap-dependent mRNA translation in a rabbit reticular cell extract assay (RRL-IVT). This series of potent, truncated analogues could serve as a promising new starting point toward the design of neutral eIF4E inhibitors with physicochemical properties suitable for cellular activity assessment.
Asunto(s)
Factor 4E Eucariótico de Iniciación/metabolismo , Guanina/análogos & derivados , Guanosina Monofosfato/análogos & derivados , Guanosina Monofosfato/farmacología , Organofosfonatos/síntesis química , Caperuzas de ARN/metabolismo , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Factor 4E Eucariótico de Iniciación/química , Guanina/síntesis química , Guanina/farmacología , Guanosina Monofosfato/síntesis química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Organofosfonatos/farmacología , Ácidos Fosforosos , Biosíntesis de Proteínas/efectos de los fármacos , Caperuzas de ARN/química , Conejos , Reticulocitos/efectos de los fármacos , Reticulocitos/metabolismo , Relación Estructura-ActividadRESUMEN
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.