USP34 as a novel target for treatment of idiopathic pulmonary fibrosis

描述（由申请方提供）：WNT信号传导的异常过度激活似乎在特发性肺纤维化（IPF）中起主要作用。过度激活的WNT信号传导的抑制剂是治疗IPF的候选物。USP 34是一种新型的去泛素化酶，已被鉴定为WNT/β-连环蛋白途径中的IPF靶标。它与Axin相互作用，并需要去泛素化Axin，使其进入细胞核，在那里它增加β-连环蛋白信号。细胞验证实验表明，USP 34通过β-连环蛋白的核定位正向调节WNT。由于WNT信号传导在IPF中升高，USP 34抑制剂将降低信号传导并具有潜在的治疗作用。Progenra开发了一种新的异肽酶测定平台，用于测量DUB活性，本文提出的工作将利用该测定通过高通量筛选发现USP 34的抑制剂。首先，将在384孔板格式中为USP 34配置测定。接下来，它将用于筛选三个小分子库-ChemDiv蛋白酶库（2000种化合物），Maybridge Hitarin多样性库（14，000种化合物）和DiverSet库（20，000种化合物）-用于USP 34的有效和选择性抑制剂。将在WNT信号传导的基于纤维化细胞的模型中以及在细胞毒性和细胞概念验证测定中评价选定命中的功效。在后期阶段，将在体内模型（小鼠的博来霉素治疗）和药代动力学研究中评价先导化合物。商业目标是一种对IPF有活性的药剂。 公共卫生相关性：WNT/β-连环蛋白信号通路与多种人类疾病有关，包括癌症和特发性肺纤维化（IPF）。对于这些疾病，WNT信号传导的抑制剂可能用作治疗剂。Progenra建议与WNT通路和肺纤维化的学术专家合作，发现一种名为USP 34的酶的抑制剂，该酶可增加IPF中的WNT信号传导。将使用Progenra的分析技术在高通量筛选中鉴定USP 34的抑制剂，并评价其作为治疗IPF的治疗剂的临床前开发。

DESCRIPTION (provided by applicant): Aberrant overactivation of WNT signaling appears to play a major role in Idiopathic Pulmonary Fibrosis (IPF). Inhibitors of overactivated WNT signaling are candidates for therapy of IPF. USP34, a novel de-ubiquitylating enzyme, has been identified as an IPF target in the WNT/(-catenin pathway. It interacts with Axin and is required to de-ubiquitylate Axin, allowing it to go to the nucleus where it increases (-catenin signaling. Cellular validation experiments have demonstrated that USP34 regulates WNT positively via nuclear localization of (-catenin. As WNT signaling is elevated in IPF, a USP34 inhibitor would decrease signaling and have a potentially therapeutic effect. Progenra has developed a novel isopeptidase assay platform for measuring DUB activity, and the work proposed here will utilize this assay to discover inhibitors of USP34 by high throughput screening. First, the assay will be configured for USP34 in a 384 well plate format. Next, it will be employed to screen three small molecule libraries - the ChemDiv Protease Library (2000 compounds), the Maybridge HitFinder diversity library (14,000 compounds), and the DiverSet Library (20,000 compounds) - for potent and selective inhibitors of USP34. The efficacy of selected hits will be evaluated in a fibrosis cell-based model of WNT signaling and in cytotoxicity and cellular proof of concept assays. In later stages, lead compounds will be evaluated in in vivo models (bleomycin treatment of mice) and pharmacokinetics studies. The commercial goal is a pharmaceutical agent active against IPF. PUBLIC HEALTH RELEVANCE: The WNT/(-catenin signaling pathway has been linked to various human diseases, including cancer and Idiopathic Pulmonary Fibrosis (IPF). For these diseases, inhibitors of WNT signaling are potentially useful as therapeutic agents. Progenra proposes to collaborate with academic experts in the WNT pathway and lung fibrosis to discover inhibitors of an enzyme called USP34, which acts to increase WNT signaling in IPF. Inhibitors of USP34 will be identified in high throughput screening using Progenra's assay technology and evaluated for preclinical development as therapeutic agents to treat IPF.