Rapid Development of a Lead Aromatic Aldehyde Derivative with both Oxygen Dependent and Novel, Oxygen Independent Anti-Sickling Effects: Building on a Paradigm Shift in Sickle Cell Disease Therapy

快速开发具有氧依赖性和新颖的、氧独立抗镰状效应的先导芳香醛衍生物：以镰状细胞病治疗范式转变为基础

• 批准号: 10765060
• 负责人: David Richard Light
• 金额: $ 97.67万
• 依托单位: ILLEXCOR THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10765060
• 关键词: Acute; Affect; Affinity; Aldehydes; American; Anemia; Animals; Anoxia; Antisickling Agents; Biological Availability; Biotin; Blood; Blood drug level result; Cessation of life; Chronic; Clinical Trials; Complex; DNA Sequence Alteration; Data; Development; Disease; Distress; Dorsal; Dosage Forms; Dose; Emulsions; Erythrocytes; Exposure to; Female; Fetal Hemoglobin; Food; Formulation; Foundations; Genus Vanilla; Goals; Half-Life; Health Care Costs; Hemoglobin; Hemolysis; Hemorrhage; Hepatotoxicity; Histopathology; Hour; Human; Hypoxia; Implant; Individual; Interruption; Kinetics; Lateral; Lead; Measures; Mus; Oral; Oral Administration; Organ; Organ failure; Oxygen; Pain; Patients; Pharmaceutical Preparations; Phase; Plasma; Polymers; Prevention; Property; Recovery; Residual Neoplasm; Reticulocyte count; Rodent; Scientist; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Skin; Solid; Structure; Study models; Suspensions; Testing; Therapeutic; Time; Toxic effect; Toxicology; Whole Blood; Work; candidate selection; clinical efficacy; disease natural history; drinking water; drug candidate; efficacy evaluation; efficacy study; hemoglobin polymer; hydroxyurea; improved; in vivo; inflammatory marker; innovation; insight; intravital microscopy; lead candidate; lead optimization; male; malformation; manufacturing scale-up; mouse model; next generation; novel; novel therapeutics; polymerization; pre-IND studies; preclinical study; premature; safety study; screening; self assembly; sickling; vanillin

Sickle Cell Disease (SCD) affects ~100,000 individuals in the US and millions more worldwide. The disease causes a range of adverse pathophysiological effects resulting in painful crises, organ failure, and eventually, premature death. Our scientists spearheaded the development of a novel class of oral anti-sickling drugs based on natural aromatic aldehydes, like vanillin from vanilla extract. This groundbreaking work demonstrated the potential of aromatic aldehydes as allosteric effectors to stabilize the high O2-affinity state of hemoglobin S (HbS) and reduce its tendency to polymerize, thereby inhibiting RBC sickling. This scientific foundation eventually led to FDA approval of the first aromatic aldehyde drug Voxelotor. While the discovery of Voxelotor was monumental for patients with this devastating condition, there are key limitations to its clinical efficacy, in particular the lack of a definitive reduction in vaso-occlusions and other disease sequalae. There is still a major opportunity for next generation oral drugs to push the limits of this therapeutic paradigm and transform SCD into a manageable chronic condition. Over the past 15 years, our team has evaluated hundreds of aromatic aldehyde compounds to identify best-in-class anti-sickling drug candidates. Novel insights from our structure-activity screening have led to the discovery of aromatic aldehyde compounds with unique polymer-destabilizing properties. More specifically, we discovered that certain aromatic aldehydes retain high anti-sickling potency even in total anoxia, whereas Voxelotor completely loses efficacy in anoxia. Unlike Voxelotor, which relies solely on increasing O2-affinity, our polymer-destabilizing compounds directly disrupt key polymer-forming contacts of HbS on the αF-helix, thus inhibiting polymer formation. Induction of fetal Hb expression in RBCs is also known to destabilize polymer formation by similarly disrupting key lateral contacts. A polymer destabilizing drug that can interrupt polymer formation pancellularly across all RBCs may be the holy grail for the SCD treatment if it can overcome key limitations to achieve unprecedented disease-modifying benefits with significantly less residual disease sequalae. Based on highly encouraging preliminary data, we have plans to advance two bona fide lead drug candidates to undergo pre-IND studies. VZHE-059 and IEX-021 are the most potent polymer destabilizing compounds discovered to date, and have other favorable lead-like properties that would suggest these candidates can become promising human drugs. VZHE-059 has already shown a clean toxicology profile. We propose a robust panel of in vivo studies in the Townes homozygous HbSS mouse model to definitively demonstrate the potential efficacy of VZHE-059 and IEX-021 for treating SCD to support advancing a lead drug into a human trial. The proposed work includes formulation of each of the study drugs followed by trials of voluntary oral administration to mice either in food chow or drinking water. Subsequently, definitive studies will evaluate the efficacy of our lead compounds in terms of reversal of chronic hemolysis and recovery of anemia, improvements in RBC half-life and deformability, and prevention of vaso-occlusion with hypoxia-reoxygenation.

镰状细胞疾病（SCD）在美国影响约100,000人，在全球范围内影响数百万。疾病 引起一系列不良病理生理影响，导致痛苦的危机，器官失败，最终导致 过早死亡。我们的科学家率先开发了一类新型口服抗ic踢药物 在天然芳香醛上，例如香草提取物的香草素。这项开创性的工作证明了 芳香醛作为变构作用的潜力，可以稳定血红蛋白S（HBS）的高O2亲密状态 并降低其聚合的趋势，从而抑制RBC的疾病。这个科学基础最终领导了 为FDA批准了第一种芳香醛药物素。虽然发现体素的人是每月一次的 对于这种毁灭性疾病的患者，其临床效率有关键局限性，特别是缺乏 最终减少了血管凝胶和其他疾病序列。接下来还有一个主要的机会 产生口服药物以推动这种治疗范式的极限，并将SCD转变为可管理的 慢性病。在过去的15年中，我们的团队评估了数百种芳香醛化合物 确定一流的反访问药物候选者。来自我们结构活动筛查的新见解具有 导致发现具有独特的聚合物二型特性的芳香醛化合物。更多的 具体而言，我们发现某些芳族醛即使在总缺氧中也保留了高抗裂缝效力， 而紫外线完全失去了缺氧的效率。与素的不同，它仅依赖于增加 O2亲和力，我们的聚合物二动化合物直接破坏HBS在 αF-螺旋，从而抑制聚合物的形成。众所周知，RBC中胎儿HB表达的诱导会破坏稳定 聚合物形成通过类似破坏钥匙的横向触点。可能中断的聚合物破坏稳定的药物 如果可以克服的话，在所有RBC上的聚合物形成可能是SCD处理的圣杯 实现前所未有的疾病改良益处的关键局限性，残留疾病明显少得多 Sequalae。基于极大鼓励的初步数据，我们计划推进两种真正的铅毒品 候选人接受预先研究的研究。 VZHE-059和IEX-021是最潜在的聚合物不稳定的 迄今为止发现的化合物，并具有其他有利的铅状特性，可以暗示这些 候选人可以成为有前途的人类药物。 VZHE-059已经显示出干净的毒理学特征。我们 提出一个强大的体内体内研究小组，纯合HBSS鼠标模型可确定 证明VZHE-059和IEX-021对治疗SCD的潜在有效性支持铅药 进入人类审判。拟议的工作包括每种研究药物的公式，然后进行试验 在食物食物或饮用水中，自愿口服给小鼠。随后，确定的研究将 根据慢性溶血和贫血的恢复，评估我们铅化合物的效率， RBC半衰期和可变形性的改善，以及通过缺氧 - 抗氧化合物预防血管结合。