Antifibrotic Therapy for Chronic Kidney Disease

描述（由申请人提供）：慢性肾脏疾病对肾病专家来说仍然是一个未解决的挑战，因为它几乎不可避免地导致终末期肾功能衰竭，这是一种危及生命的疾病，需要肾脏替代治疗。很少，如果有的话，目前实践的治疗策略反对导致肾脏疾病的纤维化的分子和细胞程序。几十年来，Abl、c-KIT、PDGFR、KDR和EGFR受体酪氨酸激酶与生长因子信号传导和血管生成有关。因此，它们已成为成功的分子靶向抗肿瘤治疗的靶标。然而，有大量证据表明，某些受体酪氨酸激酶，包括PDGFR和KDR，也可能是抗纤维化药物的有希望的靶点。虽然抗肿瘤疗法已经成功地开发用于肿瘤学，但这些小分子是否适合用作抗纤维化药物仍不清楚。Angion Biomedica已经鉴定出一种具有PDGFR和KDR抑制活性的小分子ANG3154。在肺和肾纤维化的实验模型中，口服ANG3154显示出强大的抗纤维化作用。基于这些令人信服的初步数据，目前的SBIR I期提案旨在深入分析ANG3154在实验性CKD中的抗纤维化作用。

DESCRIPTION (provided by applicant): Chronic kidney disease remains an unsolved challenge for the nephrologist, as it almost inevitably leads to end-stage renal failure, a life-threatening condition that necessitates renal replacement therapy. Few, if any, of the currently practiced therapeutic strategies oppose the molecular and cellular program of fibrosis that drives renal disease. For decades, Abl, c-KIT, PDGFR, KDR, and EGFR receptor tyrosine kinases have been implicated in growth factor signaling and angiogenesis. They have therefore been the targets for successful molecular targeted anti-neoplastic therapeutics. However, there is a substantial body of evidence that certain receptor tyrosine kinases, including PDGFR and KDR can also be promising targets for anti-fibrotic agents. While anti-neoplastic therapeutics have successfully been developed for use in oncology, it remains unclear whether these small molecules are suitable for use as antifibrotic agents. Angion Biomedica has identified ANG3154, a small molecule with PDGFR and KDR inhibitory activity. In experimental models of pulmonary and renal fibrosis, orally administered ANG3154 has exhibited powerful antifibrotic effects. Based on these compelling preliminary data, the present SBIR Phase I proposal is designed to make an in-depth analysis of the antifibrotic effects of ANG3154 in experimental CKD. PUBLIC HEALTH RELEVANCE: A small molecule orally bioactive antifibrotic has significant clinical potential for treatment of chronic kidney disease.