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

镰状细胞病（SCD）影响美国约10万人，全球数百万人。疾病 引起一系列不良的病理生理作用，导致疼痛危象、器官衰竭，最终， 过早死亡我们的科学家率先开发了一种新型的口服抗镰状病药物， 天然芳香醛，如香草精中的香草醛。这项开创性的工作证明了 芳香醛作为变构效应物稳定血红蛋白S（HbS）的高O2亲和态的潜力 并降低其镰状化倾向，从而抑制红细胞镰状化。这一科学基础最终导致了 FDA批准了第一个芳香醛类药物Voxelotor。虽然体素扫描仪的发现具有里程碑意义 对于患有这种毁灭性疾病的患者，其临床疗效存在关键限制，特别是缺乏 血管闭塞和其他疾病后遗症的明确减少。下一步仍有重大机遇 新一代口服药物，以推动这种治疗模式的极限，并将SCD转化为可管理的 慢性病在过去的15年里，我们的团队已经评估了数百种芳香醛化合物， 来确定最好的抗镰状病药物候选者。我们的结构-活性筛选的新见解 导致发现了具有独特的聚合物去稳定性质的芳族醛化合物。更 具体地说，我们发现某些芳香醛即使在完全缺氧的情况下也保持高的抗镰状化效力， 而Voxelotor在缺氧中完全失去功效。与Voxelotor不同，Voxelotor仅依赖于增加 O2-亲和力，我们的聚合物去稳定化合物直接破坏HbS在 α F-螺旋，从而抑制聚合物的形成。还已知诱导RBC中的胎儿Hb表达会使RBC不稳定， 通过类似地破坏关键的横向接触来形成聚合物。一种聚合物稳定剂， 如果能够克服所有红细胞的聚合物形成， 实现前所未有的疾病改善获益和显著减少残留疾病的关键限制 后遗症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， 候选人接受IND前研究。VZHE-059和IEX-021是最有效的聚合物去稳定剂， 化合物发现的日期，并有其他有利的铅样性能，这将表明这些 候选药物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 提出在汤斯纯合HbSS小鼠模型中进行一组强有力的体内研究，以明确地 证明VZHE-059和IEX-021治疗SCD的潜在疗效，以支持推进先导药物 进行人体试验拟议的工作包括制定每种研究药物，然后进行试验， 在食物或饮用水中对小鼠自愿口服给药。随后，明确的研究将 评价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， RBC半衰期和变形性的改善，以及缺氧-再氧合引起的血管闭塞的预防。

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.