Improvement of Sphingosine Kinase-2 Inhibitors

产品说明：血管渗漏是组织损伤的标志，并导致血浆移动到免疫介质和凝血因子侵入受损组织的血管中。如果持续存在，血管渗漏可能会加剧炎症并导致慢性和异常的伤口愈合反应。鞘氨醇1-磷酸（S1 P）是一种多效性脂质介质，在血流中循环，在那里它能增强血管屏障的完整性。 S1 P由鞘氨醇激酶合成，其以两种同种型（SphK 1和SphK 2）存在。最近，SphynKx Therapeutics发现了一种优秀的“先导”SphK 2选择性抑制剂，该抑制剂已被验证可使用循环S1 P水平的变化作为靶点结合的生物标志物来抑制体内酶。也许与直觉相反，当给予具有SphK 1和SphK 2等位基因的小鼠时，这种先导SphK 2抑制剂导致循环S1 P水平几乎加倍（即，野生型小鼠）。这一结果可能看起来很奇怪，直到人们认为SphK 2缺失小鼠的血液S1 P水平比野生型同窝出生小鼠高2-3倍（比SphK 1缺失同窝出生小鼠高约6倍）。鉴于这一发现，我们假设通过SphK 2抑制提高血液S1 P水平将改善内皮屏障功能，并停止或减缓具有显著渗漏成分的疾病的进展。更具体地说，我们专注于探索我们的SphK 2抑制剂治疗组织纤维化的治疗效用，其中血管渗漏导致促纤维化介质的持续流入，导致异常伤口愈合。尽管前景看好，但SphynKx的主要SphK 2抑制剂必须进一步优化，以将该分子推进到进一步的概念验证测试中，并进行研究性新药（IND）研究。特别是，该项目旨在提高该化合物对SphK 2的效力和同种型选择性超过SphK 1。因此，我们项目的目标是（目的1）使用药物化学优化先导化合物的结构，（目的2）使用包括体外靶筛选和体内药代动力学的算法表征候选化合物，最后（目的3）评估所选化合物在两种肾纤维化小鼠模型中防止血管渗漏和减轻纤维化的能力。如果我们成功，我们的研究将验证SphK 2作为血管渗漏和纤维化的药物靶标，并为进一步的临床前开发提供优化的SphK 2抑制剂。

DESCRIPTION: Vascular leak is a hallmark of tissue injury, and results in the movement of plasma into the interstitium where immune mediators and clotting factors invade the injured tissue. Left to persist, vascular leak can exacerbate inflammation and lead to a chronic and abnormal wound healing response. Sphingosine 1-phosphate (S1P) is a pleiotropic lipid mediator that circulates in the bloodstream where it tonically enhances vascular barrier integrity. S1P is synthesized by sphingosine kinase, which exists as two isotypes (SphK1 and SphK2). Recently, SphynKx Therapeutics discovered an excellent "lead" SphK2 selective inhibitor that has been validated to inhibit the enzyme in vivo using changes in circulating S1P level as the biomarker of target engagement. Perhaps counterintuitive, this lead SphK2 inhibitor causes circulating S1P levels to nearly double when given to mice with both SphK1 and SphK2 alleles (i.e., wild type mice). This result might seem odd until one considers that blood S1P levels in SphK2 null mice are 2-3 times higher than in wild type littermates (and about 6-fold higher than in SphK1 null littermates). Given this finding, we hypothesize that raising blood S1P levels through SphK2 inhibition will improve endothelial barrier function and halt or slow the progression of diseases with a significant leak component. More specifically, we are focused on exploring the therapeutic utility of our SphK2 inhibitors to treat tissue fibrosis, where vascular leak results in a constant influx of pro-fibrotic mediators that cause abnormal wound healing. Although promising, SphynKx's lead SphK2 inhibitor must be optimized further to advance this molecule into further proof-of-concept testing and conduct investigational new drug (IND)-enabling studies. In particular, this project seeks to improve the potency and isotype selectivity of this compound towards SphK2 over SphK1. Therefore, the goal of our project is (aim 1) to optimize the structure of the lead compound using medicinal chemistry, (aim 2) characterize candidate compounds using an algorithm that includes in vitro target screens and in vivo pharmacokinetics, and finally (aim 3) evaluate the ability of select compounds to protect against vascular leak and attenuate fibrosis in two mouse models of kidney fibrosis. If we are successful, our investigations will have validated SphK2 as a drug target in vascular leak and fibrosis, and delivered an optimized lead SphK2 inhibitor for further pre-clinical development.