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症性疾病。其发病机制尚不清楚，可能与胰腺的急性炎症和坏死有关，局部组织或器官系统的不同受累可导致全身炎症反应。每年有成千上万的人因AP住院，并发并发症。仅在美国，每年就有100万名患者因AP住院，导致7200人死亡。大多数患者病情轻微，但25%的患者病情严重，30%至50%的患者会死亡。AP最常见的原因是胆结石和大量饮酒（60%-80%）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方法是非甾体抗炎药（NSAID）和皮质类固醇、抗生素和营养补充剂。重症患者的标准治疗包括早期有创监测和复苏、预防性抗生素、营养和连续CT扫描以识别感染和坏死。对于严重急性胰腺炎没有单一有效的治疗策略。最近，尽管采用了微创技术，但坏死胰腺组织清创后的并发症仍然很常见，严重AP的死亡率仍然很高。它还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。聚（adp -核糖）聚合酶（PARP）是一种核酶，在AP的发病机制中起着重要作用。最近的研究表明，氧源性自由基在AP的发病机制中起着至关重要的作用。自由基引起的氧化应激和PARP的激活被认为是酒精引起胰腺损伤的共同机制。在胆结石和缺血性胰腺炎以及其他AP。PARP过度激活的实验模型中，消耗细胞内NAD+和ATP的浓度，从而导致细胞功能障碍和细胞死亡。抑制PARP的激活是治疗胰腺损伤最令人兴奋的研究领域之一。利用包含3d分子模型的产品发现引擎，我们成功地鉴定了两个新的小分子，它们在体外抑制PARP活性，并在体内AP和毒性损伤模型中发挥保护作用。我们的治疗策略旨在将最好的PARP抑制剂之一带入进一步的研究，并带入临床试验，以降低与严重AP相关的患者发病率和死亡率。

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.