Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.

中文翻译：

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PF-07059013：血红蛋白的非共价调节剂，用于治疗镰状细胞病

镰状细胞病（SCD）是一种遗传疾病，由成年血红蛋白（HbA）的β链上的单点突变（β6Glu→Val）引起，导致镰状血红蛋白（HbS）。在脱氧状态下，HbS聚合会导致红血球（RBC）镰状化。聚合反应和RBC镰刀菌反应的一些下游后果包括血管阻塞，溶血性贫血和中风。我们报告了HbS的非共价调节剂的设计，临床候选药物PF-07059013（23）。精子命中分子是通过虚拟筛选发现的，并通过一系列生化和生物物理研究得到证实。经过大量的优化工作，我们得出了23，一种以纳摩尔亲和力特异性结合Hb并显示出强烈分配进入RBC的化合物。在使用Townes SCD小鼠进行的为期2周的多剂量研究中，有23例显示与载体治疗的小鼠相比，镰刀减少了37.8％（±9.0％）。23（PF-07059013）已进入1期临床试验。