RESUMEN
The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be "undruggable," between switch I and II on RAS; 1 is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.
Asunto(s)
Descubrimiento de Drogas , Preparaciones Farmacéuticas/química , Proteínas Proto-Oncogénicas p21(ras)/química , Guanosina Trifosfato/metabolismo , Humanos , Modelos Moleculares , Nanopartículas/químicaRESUMEN
Herein we report a method for the synthesis of indazoles from readily available 2-aminomethyl-phenylamines via N-N bond-forming oxidative cyclization. Inspired by indazole formation initially observed as a side product by N. Coskun et al. we developed a robust protocol to access indazoles in all three tautomeric forms. The method selectively gives access to various 2-substituted 2H-indazoles which are frequently used in drug design, and we also demonstrated its applicability to less studied 3H-indazoles.
RESUMEN
The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.
Asunto(s)
Antineoplásicos/química , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Descubrimiento de Drogas , Clorhidrato de Fingolimod , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Glicoles de Propileno/química , Glicoles de Propileno/farmacología , Ratas , Receptores de Lisoesfingolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/química , Esfingosina/farmacología , Relación Estructura-ActividadRESUMEN
Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel-Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC50 of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems.
Asunto(s)
Quinasa 1 de Adhesión Focal/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Recombinantes/metabolismo , Línea Celular Tumoral , Proliferación Celular , Quinasa 1 de Adhesión Focal/genética , Quinasa 1 de Adhesión Focal/metabolismo , Humanos , Ligandos , Proteolisis , Interferencia de ARNRESUMEN
Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3Kgamma, have become attractive drug targets for inflammatory and autoimmune diseases. Here, we disclose a novel series of furan-2-ylmethylene thiazolidinediones as selective, ATP-competitive PI3Kgamma inhibitors. Structure-based design and X-ray crystallography of complexes formed by inhibitors bound to PI3Kgamma identified key pharmacophore features for potency and selectivity. An acidic NH group on the thiazolidinedione moiety and a hydroxy group on the furan-2-yl-phenyl part of the molecule play crucial roles in binding to PI3K and contribute to class IB PI3K selectivity. Compound 26 (AS-252424), a potent and selective small-molecule PI3Kgamma inhibitor emerging from these efforts, was further profiled in three different cellular PI3K assays and shown to be selective for class IB PI3K-mediated cellular effects. Oral administration of 26 in a mouse model of acute peritonitis led to a significant reduction of leukocyte recruitment.
Asunto(s)
Furanos/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Tiazolidinedionas/síntesis química , Enfermedad Aguda , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/fisiología , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase Ib , Cristalografía por Rayos X , Furanos/química , Furanos/farmacología , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Monocitos/efectos de los fármacos , Monocitos/fisiología , Neutrófilos/inmunología , Peritonitis/inducido químicamente , Peritonitis/tratamiento farmacológico , Peritonitis/inmunología , Fosfatidilinositol 3-Quinasas/química , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Relación Estructura-Actividad , Tiazolidinedionas/química , Tiazolidinedionas/farmacología , TioglicolatosRESUMEN
We report a novel chemical class of potent oxytocin receptor antagonists showing a high degree of selectivity against the closely related vasopressin receptors (V1a, V1b, V2). An initial compound, 7, was shown to be active in an animal model of preterm labor when administered by the intravenous but not by the oral route. Stepwise SAR investigations around the different structural elements revealed one position, the arenesulfonyl moiety, to be amenable to structural changes. Consequently, this position was used to introduce a variety of substituents to improve the physicochemical properties. Some of the resulting analogues were found to be superior to 7 both in terms of potency in vitro and aqueous solubility, which translated into significantly improved efficacy in the animal model after intravenous and oral administration. The best compound, 73, potently inhibited oxytocin-induced uterine contractions in nonpregnant rats and reduced spontaneous uterine contractions in late-term pregnant rats.