MECHANISM OF ACTION OF HALOFUGINONE AS A NOVEL THERAPEUTIC

描述（由申请人提供）：使用小分子来操纵体内代谢功能已经成为治疗多种疾病病理的重要新方法。氨基酸饥饿反应（amino acid hunger response， AAR）是一种控制多种代谢和细胞保护功能以响应氨基酸可用性限制的信号通路。在我们的初步实验中，我们发现halofuginone是一种对多种动物疾病模型（包括纤维化和血管生成）有效的小分子，是一种有效的特异性AAR激活剂。我们还发现halofuginone通过一种新的机制激活AAR，并且独立于AAR信号传导的最佳介质。通过这种新的信号机制，HF调节了多种先前描述的与疾病病理或发病机制相关的细胞行为。我们还发现了HF对体外和体内促炎t细胞分化的一种新的特异性作用。HF以其体外效应预测的方式改变体内t细胞群。在自身免疫小鼠模型中，心衰降低了炎症病理，表明心衰作为一种新的治疗自身免疫性和慢性炎症性疾病的药物具有很强的潜力。这些观察结果为了解HF和其他具有类似分子靶点的小分子如何在治疗与慢性炎症疾病相关的病理方面具有新的和意想不到的用途提供了令人兴奋的新机会。

DESCRIPTION (provided by applicant): The use of small molecules to manipulate metabolic function in vivo has emerged as an important new approach to therapy for a wide range of disease pathologies. The amino acid starvation response (AAR) is a signaling pathway that controls a variety metabolic and cytoprotective functions in response to the restriction of amino acid availability. In our preliminary experiments we have found that halofuginone, a small molecule with efficacy in a variety of animal disease models involving fibrosis and angiogenesis, is a potent and specific activator of the AAR. We have also found that halofuginone activates the AAR through a novel mechanism, and acts independently of the best characterized mediator of AAR signaling. Through this novel signaling mechanism, HF regulates a variety of previously described cell behaviors associated with disease pathology or pathogenesis. We have also identified a novel, specific effect of HF on the differentiation in vitro and in vivo pro-inflammatory T-cells. HF alters T-cell populations in vivo in a way predicted by its effects in vitro. HF reduces inflammatory pathology in a mouse model of autoimmunity, indicating that HF has strong potential as a new class of therapeutic for autoimmune and chronic inflammatory disease. These observations open an exciting new set of opportunities for understanding how HF, and other small molecules with similar molecular targets, may have new and unexpected uses for the treatment of pathology associated with chronic inflammatory disease.