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)在美国影响约10万人，在全球范围内影响数百万人。这种病 导致一系列不利的病理生理影响，导致痛苦的危象，器官衰竭，最终， 过早死亡。我们的科学家带头开发了一种新型的口服抗呕吐药物 天然芳香醛，如香草提取物中的香草醛。这项开创性的工作展示了 芳香醛作为变构效应稳定血红蛋白S高亲和力状态的潜力 并降低其聚合倾向，从而抑制红细胞病态。这一科学基础最终导致了 以FDA批准的第一个芳香醛药物Voxelotor。虽然Voxelotor的发现是不朽的 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绝对减少。下一步仍有一个重大机会 产生口服药物，以推动这一治疗范式的极限，并将SCD转变为可管理的 慢性疾病。在过去的15年里，我们的团队评估了数百种芳香醛化合物 以确定一流的抗镰刀药候选药物。我们从结构活性筛选中获得的新见解 导致发现了具有独特的聚合物不稳定性能的芳香醛化合物。更多 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着很高的抗镰刀效力， 而Voxelotor在缺氧时完全失效。与Voxelotor不同，Voxelotor仅依靠增加 O2-亲和力，我们的聚合物不稳定化合物直接破坏HBS在表面上形成聚合物的关键接触 α的F-螺旋，从而抑制聚合物的形成。诱导胎儿Hb在红细胞中的表达也是已知的破坏稳定性的因素 通过类似地破坏关键的侧向接触来形成聚合物。一种聚合物不稳定药物，可以中断 如果SCD治疗能够克服的话，跨所有红细胞的聚合物形成可能是SCD治疗的圣杯 在显著减少残留疾病的情况下实现前所未有的疾病改善效益的关键限制 后遗症。基于非常鼓舞人心的初步数据，我们计划推出两种真正的铅药物 参加IND预科学习的考生。VZHE-059和IEX-021是最强的聚合物 到目前为止发现的化合物，并具有其他良好的类似铅的性质，这表明这些 候选人可能会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 建议在Townes纯合子HbSS小鼠模型中进行可靠的活体研究小组，以明确 展示VZHE-059和IEX-021治疗SCD的潜在疗效以支持推进先导药物 变成了人体试验。拟议的工作包括每种研究药物的配方，然后进行试验 自愿给小鼠灌胃食物或饮用水。随后，权威性研究将 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疗效， 改善红细胞半衰期和变形性，防止缺氧-复氧引起的血管闭塞。

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.