Preclinical Development of Selective PKC_epsilon Inhibitors to Treat Alcoholism

酒精中毒和酒精滥用是最常见的药物滥用形式，影响了美国约8%的人口，每年的费用约为1840亿美元。目前的治疗一般包括旨在康复和减少与酒精有关的问题的社会心理疗法，以及使用数量有限的批准药物的药物疗法。虽然目前的治疗可以有效地减少酒精消费，但据估计，40-70%的患者在治疗后一年内恢复过度饮酒。这部分是由于目前批准的药物及其副作用的有效性有限，导致其使用依从性差。显然，需要开发更有效的药物。通过对PKC_β缺乏的小鼠和用PKC_β肽抑制剂治疗的大鼠的研究获得的大量临床前数据为开发PKC_β抑制剂以减少酒精自我给药和与酒精性多发性神经病相关的疼痛提供了强有力的案例。此外，有证据表明，PKC_κ抑制剂可用于治疗焦虑，这通常与酗酒有关，并可能导致过度饮酒。该提案的重点是临床前开发一类新型的小有机化合物，作为酶PKC_κ的抑制剂。目前，没有选择性的PKC_β抑制剂可以全身给药并穿过血脑屏障。基于我们的I期SBIR研究中的多性质计算模型和湿实验室验证，水溶性小分子VMD-C620被鉴定为一种有效的和相对选择性的“变构”PKC_β抑制剂，其作用可逆且与ATP和底物非竞争性。VMD-C620在酒精性多发性神经病的实验动物模型中也显示出有效性，并且在针对相关激酶（包括高度相关的PKC_κ）进行测定时表现出高度特异性。其独特的分子支架非常适合通过药物和计算化学进行修饰和优化。这些独特的特性使VMD-C620成为进一步衍生，优化和开发用于酒精使用障碍潜在治疗的优秀候选药物。该项目旨在开发更有效的VMD-C620衍生物，并在与酒精使用障碍相关的临床前药代动力学和动物疾病模型中对其进行研究。这项工作将为未来的研究奠定基础，这将完成临床前开发，以允许在人类中测试新型PKC_κ抑制剂作为治疗酒精使用障碍的新的和改进的药物。

DESCRIPTION (provided by applicant): Alcoholism and alcohol abuse are the most common forms of drug abuse and effect about 8% of the U.S. population at a cost of approximately $184 billion a year. Current treatment generally consists of psychosocial therapies aimed at rehabilitation and reducing alcohol-associated problems and pharmacotherapy with a limited number of approved drugs. While current treatment can be effective in reducing alcohol consumption, it is estimated that 40-70% of patients return to excessive drinking within a year after treatment. This is partly due to the modest effectiveness of currently approved medications and their side effects, which contribute to poor compliance with their use. Clearly, there is a need to develop more effective drugs. A large body of preclinical data available through studies of mice deficient in PKC_epsilon and rats treated with a peptide inhibitor of PKC_epsilon provides a strong case for development of PKC_epsilon inhibitors to reduce alcohol self-administration and pain associated with alcoholic polyneuropathy. In addition, evidence indicates that PKC_epsilon inhibitors could be useful for the treatment of anxiety, which is commonly associated with alcoholism and may contribute to excessive drinking. This proposal is focused on the preclinical development of a novel class of small organic compounds that act as inhibitors of the enzyme PKC_epsilon. Currently, there are no selective inhibitors of PKC_epsilon that can be administered systemically and cross the blood-brain barrier. Based on combined multi-property computational modeling and wet-lab verification in our Phase I SBIR study, a water soluble small organic molecule, VMD-C620 was identified as an effective and relatively selective "allosteric" PKC_epsilon inhibitor acting reversibly and noncompetitively with ATP and substrate. VMD-C620 was also shown to be efficacious in an experimental animal model of alcoholic polyneuropathy and exhibited high specificity when assayed against related kinases, including the highly related PKC_epsilon. Its distinctive molecular scaffold is very amenable to modification and optimization by medicinal and computational chemistries. These unique properties make VMD-C620 an excellent candidate to be further derived, optimized and developed for the potential treatment of alcohol use disorders. The project proposed here is to develop more potent derivatives of VMD-C620 and study them in preclinical pharmacokinetic and animal disease models relevant to alcohol use disorders. This work will form the basis for future studies, which will complete preclinical development to allow testing of a novel PKC_epsilon inhibitor in humans as a new and improved agent for treatment of alcohol use disorders.