Targeting the Integrated Stress Response effector ATF4 for mitigation of treatment-induced fibrosis

摘要 Veltion Treateutics LLC(VTP)正在开发新的、有效的和特定的ATF4抑制剂作为抗纤维化药物 药物，利用辐射诱导的肠和肺纤维化作为最初的概念验证适应症 预防性设置。Veltion Treateutics正在与加州大学的康斯坦丁诺斯·库梅尼斯博士合作 宾夕法尼亚州，肿瘤学研究的先驱以及ATF4的促肿瘤和促转移作用 至于筛选和开发辐射防护剂和减震剂。他发表了大量关于 辐射诱导纤维化的病理生物学，并与co-I，Melpo Christofidou博士广泛合作- Solomidou关于化学诱导的纤维化。化疗/放射治疗的主要局限性之一是 正常组织，如肠和肺，以溃疡、出血、肺炎和纤维化的形式出现， 多与不可逆转的终末期慢性炎症有关。此外，纤维化也是一个重要的 胰腺癌和肺癌的特征，已被证明与更严重的疾病相关 结果。 活化的成纤维细胞已被表征为主要的细胞类型，有助于发病和 放化疗后肠和肺纤维化的表现。使用有条件淘汰法的初步结果 ATF4模型显示ATF4的表达与脑功能激活呈显著正相关。 成纤维细胞，以ATF4依赖的胶原水平和沉积调节为特征。Veltion治疗公司 LLC认为，用小分子抑制剂干扰ATF4的活性可能会导致抑制ATF4的起始和 纤维化的进展。 我们的团队已经开发了一种强大的基于细胞的筛选，并正在完成对44,000个精选文库的筛选 预先选定的小分子。通过对前2,500个化合物的筛选，我们鉴定出8个化合物具有IC50 在针对ATF4的低微米范围内。在这项申请中，我们建议：(A)扩大我们对以下物质的抑制物检测 ATF4活性与44,000个化合物文库的比对，并验证所鉴定的30-50的特异性和效力 体外试验中胶原生成和沉积的抑制物(B)使用3种最有效的抑制物 目的：测定其在小鼠放射性肝纤维化模型中的最大抑菌浓度和药效。积极的结果来自 这些研究将构成PK/PD和毒性研究以及针对化疗的更广泛测试的基础。 在II期STTR的其他纤维化模型中诱导的纤维化。该团队假设，拟议的工作 将导致更好地保护正常组织，使化疗/放射治疗更有效地预防 癌症和改善数百万癌症患者的生活质量。

Summary Veltion Therapeutics LLC (VTP) is developing novel, potent and specific inhibitors of ATF4 as antifibrotic agents, utilizing radiation-induced intestinal and lung fibrosis as initial, proof-of-concept indications in the preventive setting. Veltion Therapeutics is collaborating with Dr. Constantinos Koumenis at the University of Pennsylvania, a pioneer in oncology research and the pro-tumorigenic and pro-metastatic role of ATF4 as well as for screening and developing radioprotectors and mitigators. He has published extensively on the pathobiology of radiation-induced fibrosis, and has collaborated extensively with co-I, Dr. Melpo Christofidou- Solomidou on chemical-induced fibrosis. One of the major limitations of chemo/radiotherapy is the toxicity in normal tissues such as the intestine and lung, in the form of ulceration, bleeding, pneumonitis and fibrosis, which is mostly associated with the irreversible end-stage chronic inflammation. Moreover, fibrosis is also an important characteristic of pancreatic (PanCa) and lung cancers that has been shown to correlate with worse disease outcomes. Activated fibroblasts have been characterized as the major cell type that contribute to the onset and manifestation of intestinal and lung fibrosis post-chemoradiation. Preliminary results using a conditional knockout ATF4 model showed a strong positive correlation between ATF4 expression and functional activation of fibroblasts, characterized by ATF4-dependent regulation of collagen levels and deposition. Veltion Therapeutics LLC believes that disrupting ATF4 activity with small molecule inhibitors could lead to inhibition of the onset and progression of fibrosis. Our team has developed a robust cell-based screen and is completing screening of a curated library of 44,000 preselected small molecules. With the first 2,500 compounds screened, we have identified 8 compounds with IC50 in the low µM range against ATF4. In this application, we propose to: (a) Expand our assay for inhibitors of ATF4 activity to a 44,000 compound library and validate the specificity and potency of 30-50 identified inhibitors in in vitro assays for collagen production and deposition (b) Use the 3 most effective inhibitors to determine their MTD and efficacy in mouse models of radiation-induced fibrosis. Positive results from these studies will form the basis of PK/PD and toxicity studies as well as broader testing against chemotherapy- induced fibrosis in additional models of fibrosis in a Phase II STTR. The team, postulates that the proposed work will lead to better protection of normal tissues rendering chemo/radiotherapy treatments more effective against malignancies and improve the quality of life of millions of cancer patients.