RESUMO
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).
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias/tratamento farmacológico , Piperazinas/farmacologia , Pirróis/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Tiofenos/farmacologia , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/metabolismo , Fosforilação/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Peptídeos/química , Células CACO-2 , Humanos , Membranas Artificiais , PermeabilidadeRESUMO
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.
Assuntos
Descoberta de Drogas , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Tiofenos/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/química , Inibidores de Proteínas Quinases/química , Pirróis/química , Bibliotecas de Moléculas Pequenas/química , Tiofenos/químicaAssuntos
Antimitóticos/síntese química , Inibidores Enzimáticos/síntese química , Macrolídeos/síntese química , Compostos de Espiro/síntese química , Antimitóticos/química , Cristalografia por Raios X , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Macrolídeos/química , Conformação Molecular , Compostos de Espiro/químicaRESUMO
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.