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

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.