Small Molecule Selective HDAC3 Inhibitors as a Novel Therapy for PTSD

 描述(申请人提供)：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，长时间暴露疗法(PE，认知行为疗法的一种形式)，以及最近采用的将PE/CBT与药物结合以增强恐惧消退学习的范式，但这些药物治疗方法取得了好坏参半的结果，迫切需要更广泛的有效药物来治疗慢性创伤后应激障碍。随着对创伤后应激障碍作为一种学习和记忆障碍的普遍认识，以及一种特定的恐惧反射障碍的具体理解，开发针对恐惧消退机制的新药物疗法的机会扩展到目前作用于突触受体水平的药物之外，具有令人兴奋的潜力。越来越多的工作表明，在多种啮齿动物模型中，由非特异性HDAC抑制剂(如SAHA(Vorinostat)、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恐惧消退。问题是，所有FDA批准的和目前临床前的HDAC抑制剂(A)没有足够的异构体选择性(抑制11种HDAC异构体中的许多)，(B)对于非肿瘤应用不安全(由HDAC1/2抑制和靶外效应共同驱动的毒性)和(C)具有较差的中枢神经系统类药物特性。需要高度异构体选择性的HDAC抑制剂来降低这些风险并增加治疗窗口。我们认为HDAC3是最佳靶点，因为(I)对HDAC3的遗传或药物抑制可持久地增强长期记忆，(Ii)HDAC1/2/3选择性抑制剂(CI-994)可增加突触可塑性，减弱远程恐惧记忆，并增强恐惧条件作用下的经典小鼠模型的消退；(Iii)HDAC3与HDAC1和2的同源性最低，为高异构体选择性提供了独特而独特的合理设计方法；以及(Iv)KDAc Treeutics的HDAC3选择性抑制剂显示出更高的安全性和耐受性，缓解了HDAC1/2抑制所驱动的已知剂量限制毒性。我们的领先开发候选药物KDAC0001是一种新型的高度优化的HDAC3选择性抑制剂，已在体外和体内进行了广泛的表征，具有初步的临床前ADME/PK/毒理学特征，良好的中枢神经系统药物特性和学习记忆范例的初步疗效。因此，有了选择性抑制剂，我们就可以对HDAC3选择性抑制在增强恐惧条件反射模型中的消退(速度和持久性)方面安全有效的假设进行重点评估。这些拟议的I期SBIR研究不仅将测试这些分子在创伤后应激障碍中的应用和潜在的临床转化，而且还将首次评估这种机制(HDAC3抑制)在使用高HDAC3选择性抑制剂增强恐惧消退方面的作用。我们的长期目标是开发一种HDAC3选择性抑制剂，作为一种新的小分子疗法，可以增强PE或CBT，以增强创伤后应激障碍的消退学习，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.