2. Academic Validation
  3. Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

  • J Med Chem. 2018 Feb 8;61(3):650-665. doi: 10.1021/acs.jmedchem.7b01375.
Pei-Pei Kung,  Patrick Bingham,  Alexei Brooun,  Michael Collins,  Ya-Li Deng,  Dac Dinh,  Connie Fan,  Ketan S Gajiwala,  Rita Grantner,  Hovhannes J Gukasyan,  Wenyue Hu,  Buwen Huang,  Robert Kania,  Susan E Kephart,  Cody Krivacic,  Robert A Kumpf,  Penney Khamphavong,  Manfred Kraus,  Wei Liu,  Karen A Maegley,  Lisa Nguyen,  Shijian Ren 1,  Dan Richter,  Robert A Rollins 2,  Neal Sach,  Shikhar Sharma,  John Sherrill,  Jillian Spangler,  Albert E Stewart,  Scott Sutton,  Sean Uryu,  Dominique Verhelle,  Hui Wang,  Shuiwang Wang 1,  Martin Wythes,  Shuibo Xin 1,  Shinji Yamazaki,  Huichun Zhu,  JinJiang Zhu,  Luke Zehnder,  Martin Edwards
Affiliations

Affiliations

  • 1 WuXi AppTec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 2 Pfizer Global Research and Development , 401 N. Middletown Road, Pearl River, New York 10965, United States.
PMID: 29211475 DOI: 10.1021/acs.jmedchem.7b01375
Abstract

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

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