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.

镰状细胞病 (SCD) 影响美国约 100,000 人，以及全球数百万人。 引起一系列不利的病理生理效应，导致痛苦的危机、器官衰竭，并最终， 我们的科学家率先开发了一类新型口服抗镰状化药物。 这项开创性的工作证明了天然芳香醛，例如香草提取物中的香草醛。 芳香醛作为变构效应物稳定血红蛋白 S (HbS) 高 O2 亲和状态的潜力 并降低其聚合倾向，从而抑制红细胞镰状化，这一科学基础最终导致了这一结果。 FDA 批准了第一个芳香醛药物 Voxelotor，而 Voxelotor 的发现具有里程碑意义。 对于患有这种毁灭性疾病的患者来说，其临床疗效存在关键限制，特别是缺乏 明确减少血管闭塞和其他疾病后遗症 下一步仍然有重大机会。 新一代口服药物突破了这种治疗模式的极限，并将 SCD 转变为可控制的疾病 在过去的 15 年里，我们的团队评估了数百种芳香醛化合物。 从我们的结构活性筛选中发现了一流的抗镰状病候选药物。 导致发现了具有独特的聚合物不稳定特性的芳香醛化合物。 具体来说，我们发现某些芳香醛即使在完全缺氧的情况下也能保持高抗镰状化效力， 而 Voxelotor 在缺氧时完全失去功效，而 Voxelotor 完全依赖于增加。 O2 亲和力，我们的聚合物不稳定化合物直接破坏 HbS 上的关键聚合物形成接触 αF-螺旋，从而抑制红细胞中胎儿 Hb 表达的诱导，也会破坏稳定性。 通过类似地破坏关键横向接触来形成聚合物，一种可以中断聚合物不稳定的药物。 如果能够克服所有红细胞的全细胞聚合物形成可能是 SCD 治疗的圣杯 在显着减少残留疾病的情况下实现前所未有的疾病缓解益处的关键限制 基于非常令人鼓舞的初步数据，我们计划推出两种真正的先导药物。 进行 IND 前研究的候选药物是最有效的聚合物去稳定剂。 迄今为止发现的化合物，并具有其他有利的类铅特性，表明这些 VZHE-059 已显示出良好的毒理学特征。 提出了在 Townes 纯合子 HbSS 小鼠模型中进行一组强有力的体内研究，以明确 证明 VZHE-059 和 IEX-021 治疗 SCD 的潜在功效，以支持先导药物的开发 拟议的工作包括配制每种研究药物，然后进行试验。 随后，将进行明确的研究，将其通过食物或饮用水自愿口服给小鼠。 评估我们的先导化合物在逆转慢性溶血和恢复贫血方面的功效， 改善红细胞半衰期和变形性，并通过缺氧-复氧预防血管闭塞。