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

Ariamala Gopalsamy | Zendy; Ann Aulabaugh | Zendy; Amey Barakat | Zendy; Kevin Beaumont | Zendy; Shawn Cabral | Zendy; Daniel P. Canterbury | Zendy; Agustin CasimiroGarcia | Zendy; Jeanne S. Chang | Zendy; Ming Z. Chen | Zendy; Chulho Choi | Zendy; Robert L. Dow | Zendy; Olugbeminiyi Fadeyi | Zendy; Xidong Feng | Zendy; Scott P. France | Zendy; Roger M. Howard | Zendy; Jay M. Janz | Zendy; J. Jasti | Zendy; Reema Jasuja | Zendy; Lyn H. Jones | Zendy; Amanda KingAhmad | Zendy; Kelly M. Knee | Zendy; Jeffrey T. Kohrt | Zendy; Chris Limberakis | Zendy; Spiros Liras | Zendy; Carlos A. Martínez | Zendy; Kim F. McClure | Zendy; Arjun Narayanan | Zendy; Jatin Narula | Zendy; Jonathan J. Novak | Zendy; Thomas N. O’Connell | Zendy; Mihir D. Parikh | Zendy; David W. Piotrowski | Zendy; Olga Plotnikova | Zendy; Ralph P. Robinson | Zendy; Parag V. Sahasrabudhe | Zendy; Raman Sharma | Zendy; Benjamin A. Thuma | Zendy; Dipy M. Vasa | Zendy; Liuqing Wei | Zendy; Anne Wenzel | Zendy; Jane M. Withka | Zendy; Jun Xiao | Zendy; Hatice G. Yayla | Zendy

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

Author(s) -

Ariamala Gopalsamy,

Ann Aulabaugh,

Amey Barakat,

Kevin Beaumont,

Shawn Cabral,

Daniel P. Canterbury,

Agustin CasimiroGarcia,

Jeanne S. Chang,

Ming Z. Chen,

Chulho Choi,

Robert L. Dow,

Olugbeminiyi Fadeyi,

Xidong Feng,

Scott P. France,

Roger M. Howard,

Jay M. Janz,

J. Jasti,

Reema Jasuja,

Lyn H. Jones,

Amanda KingAhmad,

Kelly M. Knee,

Jeffrey T. Kohrt,

Chris Limberakis,

Spiros Liras,

Carlos A. Martínez,

Kim F. McClure,

Arjun Narayanan,

Jatin Narula,

Jonathan J. Novak,

Thomas N. O’Connell,

Mihir D. Parikh,

David W. Piotrowski,

Olga Plotnikova,

Ralph P. Robinson,

Parag V. Sahasrabudhe,

Raman Sharma,

Benjamin A. Thuma,

Dipy M. Vasa,

Liuqing Wei,

Anne Wenzel,

Jane M. Withka,

Jun Xiao,

Hatice G. Yayla

Publication year - 2020

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.0c01518

Subject(s) - chemistry , hemoglobin , sickle cell anemia , deoxygenated hemoglobin , cell , red blood cell , mutation , hemoglobin s , pharmacology , biochemistry , gene , medicine

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 a 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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