Acid Ceramidase, Target for Cancer

描述（由申请人提供）：酸性神经酰胺酶（AC）已被认为是癌症治疗的新靶点，因为它在调节三种关键生物活性脂质的相互转化中起关键作用；神经酰胺（Cer）、鞘氨醇（Sph）和鞘氨醇-1-磷酸（S1P）。众所周知，Cer主要作为肿瘤抑制脂质和化疗和放疗后细胞凋亡的介质。另一方面，S1P是一种促进肿瘤的脂质，可以抵消Cer的作用。重要的是，我们最近的研究发现AC在癌症治疗中是一个负面的预后因素，因为AC的过表达诱导了一种更具侵袭性的癌症表型，从而导致药物或放射耐药。利用siRNA或小分子AC抑制剂逆转AC表达清楚地表明，在体外和体内，侵袭性癌症表型减少，化疗、基因或放射治疗效果改善。在60-70%的癌症中观察到AC表达上调，包括乳腺癌、肺癌、前列腺癌、黑色素瘤、结肠癌、脑癌和口腔癌。根据ACS 2004年的统计数据，预计每年新病例总数将超过70万例。因此，由于潜在的改善临床结果的直接益处，SphingoGene公司开发的小分子AC抑制剂在商业上是可行的。因此，这个I期STTR申请的目标是开发和验证靶向AC抑制剂。为实现这一目标，将实施以下具体目标。目的1：合理设计合成抑制AC酶活性的n -烷基胺前药（E类）。目的2：测定E类化合物在体外和细胞水平的活性。目的3：确定E1类和E2-5类交流抑制剂的体内毒性、药代动力学/药效学和交流抑制活性。这项研究是由MUSC的基础科学家和SphingoGene公司合作进行的。该项目开发的药物将在癌症治疗中有直接的临床应用。公共卫生相关性：该资助产生的数据可能导致直接的临床应用。这项拨款建议开发一类新的酸性神经酰胺酶抑制剂。这些抑制剂通过改变鞘脂代谢和促进化疗、放疗或基因治疗杀死癌细胞的效果而起作用。

DESCRIPTION (provided by applicant): Acid ceramidase (AC) has been implicated as a novel target for cancer therapy because of its pivotal role in regulating interconversion of three key bioactive lipids; ceramide (Cer), sphingosine (Sph) and Sphingosine-1-Phosphate (S1P). It is well known that Cer functions predominantly as a tumor suppressor lipid and mediator of apoptosis following chemo and radio therapy. On the other hand, S1P is a tumor promoting lipid that counteracts the actions of Cer. Importantly, our recent studies identified AC as a negative prognostic factor in cancer therapy, since AC over-expression induces a more aggressive cancer phenotype which causes drug or radiation resistance. Reversal of AC expression utilizing siRNA or small molecule AC inhibitors clearly demonstrated a reduction in the aggressive cancer phenotype and improved chemo, gene or radiation therapy outcomes in vitro and in vivo. Up-regulated AC expression has been observed in 60-70% of cancers examined including in breast, lung, prostate, melanoma, colon, brain, and oral cancers. New cases per year totaling more than 700,000 patients are projected from these data based on ACS 2004 statistics. Thus, because of the potential for a direct benefit of improved clinical outcomes, the development of small molecule AC inhibitors by SphingoGene, Inc. is a commercially feasible proposition. Therefore, the goal of this phase I STTR application is to develop and validate targeted AC inhibitors. To achieve this goal the following specific aims will be carried out. Aim 1: Rationally design and synthesize N-alkylamino-prodrugs (Class E) that inhibit AC enzyme activity. Aim 2: Determine activity of Class E compounds in vitro and at the cellular level. Aim 3: Determine in vivo toxicity, pharmacokinetics/pharmacodynamics and AC inhibitory activity of lead Class E1 and E2-5 AC inhibitors. This research is a partnership between basic scientists at MUSC and SphingoGene, Inc. Drugs developed in this program will have a direct clinical application in cancer therapy. PUBLIC HEALTH RELEVANCE: The data generated by this grant may lead to a direct clinical application. This grant proposes to develop a new class of acid ceramidase inhibitors. These inhibitors function by modifying sphingolipid metabolism and facilitating the effect of chemo, radiation or gene therapy in killing cancer cells.