RESUMEN
Aberrant activation in fibroblast growth factor signaling has been implicated in the development of various cancers, including squamous cell lung cancer, squamous cell head and neck carcinoma, colorectal and bladder cancer. Thus, fibroblast growth factor receptors (FGFRs) present promising targets for novel cancer therapeutics. Here, we evaluated the activity of a novel pan-FGFR inhibitor, rogaratinib, in biochemical, cellular and in vivo efficacy studies in a variety of preclinical cancer models. In vitro kinase activity assays demonstrate that rogaratinib potently and selectively inhibits the activity of FGFRs 1, 2, 3 and 4. In line with this, rogaratinib reduced proliferation in FGFR-addicted cancer cell lines of various cancer types including lung, breast, colon and bladder cancer. FGFR and ERK phosphorylation interruption by rogaratinib treatment in several FGFR-amplified cell lines suggests that the anti-proliferative effects are mediated by FGFR/ERK pathway inhibition. Furthermore, rogaratinib exhibited strong in vivo efficacy in several cell line- and patient-derived xenograft models characterized by FGFR overexpression. The observed efficacy of rogaratinib strongly correlated with FGFR mRNA expression levels. These promising results warrant further development of rogaratinib and clinical trials are currently ongoing (ClinicalTrials.gov Identifiers: NCT01976741, NCT03410693, NCT03473756).
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Piperazinas/farmacología , Pirroles/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Tiofenos/farmacología , Animales , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Distribución Aleatoria , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We herein report the first thorough analysis of the structure-permeability relationship of semipeptidic macrocycles. In total, 47 macrocycles were synthesized using a hybrid solid-phase/solution strategy, and then their passive and cellular permeability was assessed using the parallel artificial membrane permeability assay (PAMPA) and Caco-2 assay, respectively. The results indicate that semipeptidic macrocycles generally possess high passive permeability based on the PAMPA, yet their cellular permeability is governed by efflux, as reported in the Caco-2 assay. Structural variations led to tractable structure-permeability and structure-efflux relationships, wherein the linker length, stereoinversion, N-methylation, and peptoids site-specifically impact the permeability and efflux. Extensive nuclear magnetic resonance, molecular dynamics, and ensemble-based three-dimensional polar surface area (3D-PSA) studies showed that ensemble-based 3D-PSA is a good predictor of passive permeability.
Asunto(s)
Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/metabolismo , Péptidos/química , Células CACO-2 , Humanos , Membranas Artificiales , PermeabilidadRESUMEN
Rogaratinib (BAY 1163877) is a highly potent and selective small-molecule pan-fibroblast growth factor receptor (FGFR) inhibitor (FGFR1-4) for oral application currently being investigated in phaseâ 1 clinical trials for the treatment of cancer. In this publication, we report its discovery by deâ novo structure-based design and medicinal chemistry optimization together with its pharmacokinetic profile.
Asunto(s)
Descubrimiento de Drogas , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Tiofenos/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Piperazinas/química , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Bibliotecas de Moléculas Pequeñas/química , Tiofenos/químicaAsunto(s)
Antimitóticos/síntesis química , Inhibidores Enzimáticos/síntesis química , Macrólidos/síntesis química , Compuestos de Espiro/síntesis química , Antimitóticos/química , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Macrólidos/química , Conformación Molecular , Compuestos de Espiro/químicaRESUMEN
3-Acyloxyl-2-oxopropyl ethers of umbelliferone were investigated as new fluorogenic substrates for lipases and esterases. The aliphatic primary alcohol-leaving group released the fluorescent product umbelliferone by an enolization/beta-elimination reaction similar to the triose phosphate isomerase (TIM) reaction. A similarly designed phenylacetamide provided a fluorescent probe for penicillin G acylase, whereby the enolization/beta-elimination sequence from the intermediate aminoketone was very fast and spontaneous even under acidic conditions. The corresponding epoxyketone was not fluorogenic with epoxide hydrolases (EH). These substrates represent periodate-free Clips-otrade mark substrates.