Therapeutic Potential of PARP inhibitor for Acute Pancreatitis

描述（由申请人提供）：急性胰腺炎（AP）是一种潜在致命的胰腺炎性疾病。其发病机制仍不清楚，涉及胰腺急性炎症和坏死过程，不同程度地累及区域组织或器官系统，导致全身炎症反应。AP每年导致数千例住院和连续并发症。仅在美国，每年就有超过300，000名患者因AP住院，导致7，200人死亡。在大多数患者中，病情轻微，但25%的患者遭受严重发作，30%至50%的患者将死亡。AP最常见的原因是存在胆结石和重度酒精（60%-80%）使用，导致胰腺炎症和坏死。其他原因包括创伤、感染、药物和胰腺肿瘤。对于轻度病例，标准治疗和目前的治疗是非甾体抗炎药（NSAID）和皮质类固醇，抗生素和营养补充剂。严重疾病患者的标准治疗包括早期侵入性监测和复苏，预防性抗生素，营养和系列CT扫描以确定感染和坏死。重症急性胰腺炎没有单一有效的治疗策略。近年来，尽管使用了微创技术，但坏死胰腺组织清创术后的并发症仍然很常见，严重AP的死亡率仍然很高。它也造成了沉重的经济负担;仅在美国，每年的直接成本就超过20亿美元。因此，迫切需要有效和负担得起的非手术治疗AP。多聚腺苷二磷酸核糖聚合酶（Poly（ADP-ribose）polymerase，PARP）是一种核酶，在AP的发病机制中起重要作用。近年来的研究表明，氧自由基在AP的发病机制中起着至关重要的作用。由自由基和PARP激活引起的氧化应激已被认为是酒精、胆结石和缺血性胰腺炎以及其他AP实验模型中胰腺损伤的共同机制。PARP过度活化，耗尽细胞内NAD+和ATP浓度，从而导致细胞功能障碍和细胞死亡。治疗胰腺损伤的最令人兴奋的研究领域之一是抑制PARP激活。使用包括3-D分子建模的产品发现引擎，我们成功地鉴定了两种新型小分子，其在体外抑制PARP活性，并在AP和毒性损伤的体内模型中发挥保护作用。我们的治疗策略旨在进一步研究最好的PARP抑制剂之一，并进行临床试验，以降低与严重AP相关的患者发病率和死亡率。 公共卫生相关性：胰腺炎是胰腺的一种炎症性坏死性疾病，重症胰腺炎伴有全身炎症反应，发病率和死亡率高。多聚腺苷二磷酸核糖聚合酶（Poly（ADP-ribose）polymerase，PARP）是一种核酶，在AP的发病机制中起重要作用。胰腺损伤中活性氧/氮自由基引起的DNA损伤和随后的PARP过度活化促进胰腺细胞功能障碍/细胞死亡，导致AP。目前的治疗方法不足以治疗重症AP。治疗胰腺损伤的最令人兴奋的研究领域之一是抑制PARP激活。使用三维分子模拟，我们成功地确定了两个新的PARP抑制剂。我们在当前项目中的治疗策略是在AP的两种体内模型中测试我们的主要PARP抑制剂，并确定最好的PARP抑制剂之一，以进一步进行II期研究，并可能成为临床产品。

DESCRIPTION (provided by applicant): Acute Pancreatitis (AP) is a potentially lethal inflammatory disease of the pancreas. Its pathogenesis remains obscure and is involved in a process of acute inflammation and necrosis in the pancreas, with variable involvement of regional tissues or organ systems that leads to a systemic inflammatory response. AP contributes to thousands of annual hospital admissions and consecutive complications. In the US alone, >300,000 patients are hospitalized annually with AP leading to 7,200 deaths. In the majority of patients, the condition is mild, but 25% of patients suffer a severe attack, and between 30 and 50%of the patients will die. The most common causes of AP is the presence of gallstones and heavy alcohol (60%-80%) use that cause inflammation and necrosis of the pancreas. Other causes include trauma, infections, medications, and tumors of the pancreas. For mild cases, standard therapy and current treatments are non-steroidal anti-inflammatory drugs (NSAID) and corticosteroids, antibiotics, and nutrition supplements. Standard therapy for patients with severe disease includes early invasive monitoring and resuscitation, prophylactic antibiotics, nutrition, and serial CT scanning to identify infection and necrosis. There is no single effective therapeutic strategy for severe acute pancreatitis. Recently, despite the use of less invasive techniques, complications following debridement of necrotic pancreatic tissue are still common and the mortality rate with severe AP is still high. It also inflicts a heavy economic burden; the direct cost in the US alone is more than $2 billion annually. Hence there is a critical need for effective and affordable non-surgical therapy for AP. Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme, plays an important role in the pathogenesis of AP. Recent studies have shown that oxygen-derived free radicals play a crucial role in the pathogenesis of AP. Oxidative stress caused by free radicals and activation of PARP has been proposed as a common mechanism for pancreatic injury in alcohol, gallstone and ischemic pancreatitis as well as in other experimental models of AP. PARP overactivation, depletes the intracellular concentration of NAD+ and ATP, thus leading to cellular dysfunction and cell death. One of the most exciting areas of research for the treatment of pancreatic injury is to inhibit PARP activation. Using a product discovery engine comprising 3-D molecular modeling, we successfully identified two novel small molecules that inhibit PARP activity in vitro and exerts protective effects in in vivo models of AP and toxic injury. Our therapeutic strategy is designed to bring one of the best PARP inhibitor to further study and bring to clinical trials to attenuate patient morbidity and mortality associated with severe AP. PUBLIC HEALTH RELEVANCE: Pancreatitis (AP) is an inflammatory and necrotic disease of the pancreas and severe AP is associated with systemic inflammatory response with high morbidity and mortality. Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme, plays an important role in the pathogenesis of AP. DNA damage by reactive oxygen/nitrogen free radicals in pancreatic injury and consequent over-activation of PARP promotes pancreatic cellular dysfunction/cell death leading to AP. Current therapeutic methods are insufficient for the treatment of severe AP. One of the most exciting areas of research for the treatment of pancreatic injury is to inhibit PARP activation. Using a 3-D molecular modeling, we successfully identified two novel PARP inhibitors. Our therapeutic strategy in the current project is to test our lead PARP inhibitors in two invivo models of AP and identifify one of the best PARP inhibitor to further studies in Phase II and potentially a clinical product.