PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease
PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease
复制标题
DOI：
10.1021/acs.jmedchem.0c01518
复制
发表时间：
2021-01-14
影响因子：
7.3
通讯作者：
Yayla, Hatice G.
中科院分区：
文献类型：
--
作者：
Gopalsamy, Ariamala;Aulabaugh, Ann E.;Yayla, Hatice G.
镰状细胞病（SCD）是一种由成人血红蛋白(HbA) β链上的单点突变（β 6 Glu -> Val）引起的遗传性疾病，导致镰状血红蛋白（HbS）。在脱氧状态下，HbS的聚合导致红细胞（RBC）的镰状坏死。聚合和红细胞镰状细胞的下游后果包括血管阻塞、溶血性贫血和中风。我们报道了一种非共价HbS调节剂的设计，临床候选药物PF-07059013（23）。通过虚拟筛选发现并通过一系列生物化学和生物物理研究证实了该分子。经过大量的优化工作，我们得到了23，这是一种以纳米摩尔亲和力特异性结合Hb的化合物，并显示出强的红细胞分裂。在对Townes SCD小鼠进行的为期2周的多次给药研究中，与对照剂处理小鼠相比，23显示镰状细胞坏死减少37.8%（+/- 9.0%）。23 （PF-07059013）已进入1期临床试验。
Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (beta 6 Glu -> Val) on the beta-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.