2. Academic Validation
  3. 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

  • J Med Chem. 2021 Jan 14;64(1):326-342. doi: 10.1021/acs.jmedchem.0c01518.
Ariamala Gopalsamy 1,  Ann E Aulabaugh 2,  Amey Barakat 3,  Kevin C Beaumont 4,  Shawn Cabral 2,  Daniel P Canterbury 2,  Agustin Casimiro-Garcia 1,  Jeanne S Chang 2,  Ming Z Chen 2,  Chulho Choi 2,  Robert L Dow 1,  Olugbeminiyi O Fadeyi 2,  Xidong Feng 2,  Scott P France 2,  Roger M Howard 2,  Jay M Janz 3,  Jayasankar Jasti 2,  Reema Jasuja 3,  Lyn H Jones 1,  Amanda King-Ahmad 5,  Kelly M Knee 3,  Jeffrey T Kohrt 2,  Chris Limberakis 2,  Spiros Liras 1,  Carlos A Martinez 6,  Kim F McClure 1,  Arjun Narayanan 1,  Jatin Narula 4,  Jonathan J Novak 5,  Thomas N O'Connell 2,  Mihir D Parikh 2,  David W Piotrowski 2,  Olga Plotnikova 2,  Ralph P Robinson 2,  Parag V Sahasrabudhe 2,  Raman Sharma 5,  Benjamin A Thuma 2,  Dipy Vasa 7,  Liuqing Wei 2,  A Zane Wenzel 2,  Jane M Withka 2,  Jun Xiao 2,  Hatice G Yayla 2
Affiliations

Affiliations

  • 1 Pfizer Medicine Design, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States.
  • 2 Pfizer Medicine Design, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States.
  • 3 Rare Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States.
  • 4 Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States.
  • 5 Primary Pharmacology Group, Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States.
  • 6 Medicinal Sciences, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States.
  • 7 Drug Product Design, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States.
PMID: 33356244 DOI: 10.1021/acs.jmedchem.0c01518
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.

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