RESUMEN
BRAFV600E mutations occur in â¼10% of colorectal cancer cases, are associated with poor survival, and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT colorectal cancer. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n = 31; validation set: n = 26) colorectal cancer, and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT colorectal cancer subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and UPR pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT colorectal cancer cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis, and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT colorectal cancer. Mol Cancer Ther; 17(6); 1280-90. ©2018 AACR.
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Respuesta de Proteína Desplegada/efectos de los fármacos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Biomarcadores de Tumor , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/genética , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Sistema de Señalización de MAP Quinasas , Modelos Biológicos , Oligopéptidos/farmacología , Pronóstico , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismoRESUMEN
This Letter describes the continued SAR exploration of small molecule Legumain inhibitors with the aim of developing a potent and selective in vitro tool compound. Work continued in this Letter explores the use of alternative P2-P3 linker units and the P3 group SAR which led to the identification of 10t, a potent, selective and cellularly active Legumain inhibitor. We also demonstrate that 10t has activity in both cancer cell viability and colony formation assays.
Asunto(s)
Cisteína Endopeptidasas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Supervivencia Celular/efectos de los fármacos , Cisteína Endopeptidasas/química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Estructura MolecularRESUMEN
Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series.
Asunto(s)
Amidas/farmacología , Analgésicos no Narcóticos/síntesis química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Analgésicos no Narcóticos/farmacocinética , Animales , Disponibilidad Biológica , Humanos , Conformación Molecular , Dolor/tratamiento farmacológico , Quinazolinas/síntesis química , Quinazolinas/farmacología , Ratas , Solubilidad , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacologíaRESUMEN
Based on a series of diaryl amides the corresponding inverse amides have been found to be potent TRPV1 receptor antagonists. Benzimidazole and indazolone derivatives prepared retained good potency in vitro and indazolone 4a was identified as a novel TRPV1 receptor antagonist suitable for evaluating orally in animal models of analgesia.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Imidazoles/química , Imidazoles/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Aminas/química , Bencimidazoles/síntesis química , Humanos , Imidazoles/síntesis química , Estructura Molecular , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.
