7JXZ

Structure of HbA with compound (S)-4

Summary for 7JXZ

• Entry DOI: 10.2210/pdb7jxz/pdb
• Descriptor: Hemoglobin subunit alpha, Hemoglobin subunit beta, PROTOPORPHYRIN IX CONTAINING FE, ... (8 entities in total)
• Functional Keywords: hemoglobin, oxygen transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 66829.56

Authors

Jasti, J. (deposition date: 2020-08-28, release date: 2021-01-13, Last modification date: 2023-10-18)

Primary citation

Gopalsamy, A.,Aulabaugh, A.E.,Barakat, A.,Beaumont, K.C.,Cabral, S.,Canterbury, D.P.,Casimiro-Garcia, A.,Chang, J.S.,Chen, M.Z.,Choi, C.,Dow, R.L.,Fadeyi, O.O.,Feng, X.,France, S.P.,Howard, R.M.,Janz, J.M.,Jasti, J.,Jasuja, R.,Jones, L.H.,King-Ahmad, A.,Knee, K.M.,Kohrt, J.T.,Limberakis, C.,Liras, S.,Martinez, C.A.,McClure, K.F.,Narayanan, A.,Narula, J.,Novak, J.J.,O'Connell, T.N.,Parikh, M.D.,Piotrowski, D.W.,Plotnikova, O.,Robinson, R.P.,Sahasrabudhe, P.V.,Sharma, R.,Thuma, B.A.,Vasa, D.,Wei, L.,Wenzel, A.Z.,Withka, J.M.,Xiao, J.,Yayla, H.G.
PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.
J.Med.Chem., 64:326-342, 2021

PubMed 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 (). 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 , 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, showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. (PF-07059013) has advanced to phase 1 clinical trials.

PubMed: 33356244
DOI: 10.1021/acs.jmedchem.0c01518

Experimental method

X-RAY DIFFRACTION (2.23 Å)