Small Molecule Selective HDAC3 Inhibitors as a Novel Therapy for PTSD

 创伤后应激障碍（PTSD）是一个主要的健康问题，每年影响超过500万美国人。尽管行为治疗方法取得了进展（例如，长期暴露疗法（PE，认知行为疗法（CBT）的一种形式）和最近采用的将PE/CBT与药物组合以增强恐惧消退学习的范例，这些药物治疗方法取得了混合的成功，并且迫切需要更广泛的用于慢性PTSD的有效药物。随着对创伤后应激障碍作为一种学习和记忆障碍的认识逐渐加深，特别是恐惧反射障碍，开发新的药物治疗靶向恐惧消退机制的机会，以超越目前作用于突触受体水平的药物，具有令人兴奋的潜力。越来越多的研究表明，由非特异性HDAC抑制剂（如SAHA（伏立诺他），丙戊酸（VPA）或丁酸钠（NaB））驱动的表观遗传效应可以促进和增强多种啮齿动物模型中的恐惧消退。问题是所有FDA批准的和目前的临床前HDAC抑制剂（a）没有足够的同种型选择性（抑制11种HDAC同种型中的许多种），（B）对于非肿瘤应用不安全（由HDAC 1/2抑制和脱靶效应两者驱动的毒性）和（c）具有差的CNS药物样性质。需要高度异构体选择性HDAC抑制剂来减轻这些风险并增加治疗窗。我们相信HDAC 3是最好的靶点，因为（i）HDAC 3的遗传或药理学抑制持续增强长期记忆，（ii）HDAC 1/2/3选择性抑制剂（CI-994）增加突触可塑性，减弱远程恐惧记忆，并增强经典小鼠恐惧条件反射模型中的消退;（iii）HDAC 3与HDAC 1和2具有最小的同源性，提供了实现高同种型选择性的独特和独特的合理设计方法;和（iv）KDAc Therapeutics的HDAC 3选择性抑制剂已证明安全性和耐受性得到改善，减轻了由HDAC 1/2抑制引起的已知剂量限制性毒性。我们的主要开发候选药物KDAC 0001是一种新型高度优化的HDAC 3选择性抑制剂，已在体外和体内进行了广泛表征，具有初步的临床前ADME/PK/毒理学特征，良好的CNS药物特性和学习和记忆模式的初始疗效。因此，有了选择性抑制剂，我们可以对HDAC 3选择性抑制在恐惧条件反射模型中增强消退（速率和持续性）安全有效的假设进行集中评估。这些提出的I期SBIR研究不仅将测试这些分子用于PTSD的应用和潜在的临床转化，而且还将提供对这种机制（HDAC 3抑制）在用高度HDAC 3选择性抑制剂增强恐惧消退中的首次评估。我们的长期目标是开发一种HDAC 3选择性抑制剂作为一种新型的小分子治疗剂，可以增强PE或CBT，以增强PTSD中的消退学习，并促进持续的恐惧抑制。

 DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is a major health problem, affecting over 5 million Americans every year. Despite advances in behavioral treatment approaches (e.g., prolonged exposure therapy (PE, a form of cognitive behavioral therapy (CBT)) and the more recently adopted paradigm of combining PE/CBT with medications to augment fear extinction learning, these pharmacotherapeutic approaches have had mixed success, and there is an urgent need for a broader array of effective medications for chronic PTSD. With the emerging understanding of PTSD as a learning and memory disorder generally, and a fear reflex disorder specifically, the opportunity to develop novel pharmacotherapeutics targeting mechanisms of fear extinction to expand beyond the current drugs that act at the level of synaptic receptors, has exciting potential. An increasing body of work has shown that epigenetic effects driven by nonspecific HDAC inhibitors (such as SAHA (Vorinostat), valproic acid (VPA) or sodium butyrate (NaB)) can facilitate and enhance fear extinction in multiple rodent models. The problem is that all FDA-approved and current pre-clinical HDAC inhibitors are (a) not sufficiently isoform selective (inhibiting many of the 11 HDAC isoforms), (b) not safe for non-oncological application (toxicity driven by both HDAC1/2 inhibition and off-target effects) and (c) have poor CNS drug-like properties. Highly isoform-selective HDAC inhibitors are needed to mitigate these risks and increase the therapeutic window. We believe HDAC3 is the best target, as (i) genetic or pharmacological inhibition of HDAC3 persistently enhances long-term memory, (ii) an HDAC1/2/3-selective inhibitor (CI-994) increased synaptic plasticity, attenuated remote fear memories, and enhanced extinction in a classic mouse model of fear conditioning; (iii) HDAC3 has the least homology to HDACs1 and 2, offering unique and distinctive rational design approaches towards high isoform selectivity; and (iv) KDAc Therapeutics' HDAC3-selective inhibitors have demonstrated improved safety and tolerability, mitigating known dose-limiting toxicities driven by HDAC1/2 inhibition. Our lead development candidate, KDAC0001, a novel highly optimized HDAC3-selective inhibitor, has been extensively characterized in vitro and in vivo, with a preliminary pre-clinical ADME/PK/ toxicological profile, good CNS drug properties and initial efficacy in learning and memory paradigms. Thus, with selective inhibitors in hand, we can enable a focused evaluation of the hypothesis that HDAC3-selective inhibition will be safe and effective in enhancing extinction (rate and persistence) in fear conditioning models. These proposed Phase I SBIR studies will not only test these molecules for application, and potential clinical translation, to PTSD, but wil also provide the first assessment of this mechanism (HDAC3 inhibition) in enhancing fear extinction with highly HDAC3-selective inhibitors. Our long-term goal is to develop an HDAC3- selective inhibitor as a novel small molecule therapeutic that would augment PE or CBT to enhance extinction learning in PTSD and promote persistent fear inhibition.