PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease

Abstract

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.

PF‐07059013: A non‐covalent hemoglobin modulator favorably impacts disease state in a mouse model of sickle cell disease

“…This dose was selected as it was expected to result in approximately 25% hemoglobin coverage. 11 At 30 minutes post the initial dose, total blood concentrations for individual animals were 2-4 mM, consistent with the low total blood clearance observed in the single dose administration studies. These values translate to approximately 40%-60% hemoglobin coverage, based on measured hemoglobin concentrations.…”

The Communication of Hit Quality Using Natural History Visualizations (NHVs)

“…4). 13 Figure 4 shows hits targeting ANAT (15)(16)(17)(18)(19) identified in a virtual screen using AtomNet, a deep convolutional neural network for structure-based drug discovery. In this case, the authors provided high-performance liquid chromatography-mass spectrometry (HPLC/MS) confirmation of their hits [purity/ id = good]; the hits were predicted to be non-promiscuous [promiscuity = good] by Hit Dexter but received warnings and cautions when analyzed in Badapple.…”

“…Other than 24 , 16 none of these hits is without blemish in the NHV. Of these compounds, the NHV warns of potential promiscuity for 22 17 and 23 , 18 which would need to be de-risked in the screening tree. Compound 26 19 has a warning in [tiering], suggesting that the physicochemical properties of this hit may need to be optimized on the way to becoming an effective probe or drug candidate.…”

Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin

“…Nevertheless, the result of the experiments and calculations presented herein cast doubt on a strategy of drug binding to the R conformation as a way of treating sickle cell disease, especially if the drug dissociates slowly. 50 Efforts aimed at developing a drug that targets polymerization should focus on the 4 other approaches: increasing HbF, decreasing MCHC, decreasing 2,3-DPG, and blocking intermolecular contacts within the sickle fiber. 16 Even though decreasing 2,3-DPG increases oxygen affinity, the left shift in the ODC is considerably less because, unlike voxelotor, it binds and dissociates rapidly 51 (supplemental Figure 2).…”