RESUMEN
Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to the rhabdoid tumor family and is usually caused by biallelic inactivation of SMARCB1, encoding a key subunit of SWI/SNF chromatin remodeling complexes. Previous studies proposed that SMARCB1 loss drives rhabdoid tumor by promoting cell cycle through activating transcription of cyclin D1 while suppressing p16. However, low cyclin D1 protein expression is observed in most ATRT patient tumors. The underlying mechanism and therapeutic implication of this molecular trait remain unknown. Here, we show that SMARCB1 loss in ATRT leads to the reduction of cyclin D1 expression by upregulating MIR17HG, a microRNA (miRNA) cluster known to generate multiple miRNAs targeting CCND1. Furthermore, we find that this cyclin D1 deficiency in ATRT results in marked in vitro and in vivo sensitivity to the CDK4/6 inhibitor palbociclib as a single agent. Our study identifies a novel genetic interaction between SMARCB1 and MIR17HG in regulating cyclin D1 in ATRT and suggests a rationale to treat ATRT patients with FDA-approved CDK4/6 inhibitors. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Ciclina D1/genética , Regulación Neoplásica de la Expresión Génica , Proteínas/genética , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Teratoma/genética , Línea Celular Tumoral , Supervivencia Celular , Ciclina D1/metabolismo , Humanos , Proteínas/metabolismo , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patología , Proteína SMARCB1/metabolismo , Teratoma/metabolismo , Teratoma/patología , Regulación hacia ArribaRESUMEN
As a unique rocaglate (flavagline) natural product, aglaroxin C displays intriguing biological activity by inhibiting hepatitis C viral entry. To further elucidate structure-activity relationships and diversify the pyrimidinone scaffold, we report a concise synthesis of aglaroxin C utilizing a highly regioselective pyrimidinone condensation. We have prepared more than 40 aglaroxin C analogues utilizing various amidine condensation partners. Through biological evaluation of analogues, we have discovered two lead compounds, CMLD012043 and CMLD012044, which show preferential bias for the inhibition of hepatitis C viral entry vs translation inhibition. Overall, the study demonstrates the power of chemical synthesis to produce natural product variants with both target inhibition bias and improved therapeutic indexes.