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Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.
Jones, Katherine L; Beaumont, Dominic M; Bernard, Sharon G; Bit, Rino A; Campbell, Simon P; Chung, Chun-Wa; Cutler, Leanne; Demont, Emmanuel H; Dennis, Kate; Gordon, Laurie; Gray, James R; Haase, Michael V; Lewis, Antonia J; McCleary, Scott; Mitchell, Darren J; Moore, Susanne M; Parr, Nigel; Robb, Olivia J; Smithers, Nicholas; Soden, Peter E; Suckling, Colin J; Taylor, Simon; Walker, Ann L; Watson, Robert J; Prinjha, Rab K.
Affiliation
  • Jones KL; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Beaumont DM; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Bernard SG; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Bit RA; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Campbell SP; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Chung CW; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Cutler L; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Demont EH; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Dennis K; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Gordon L; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Gray JR; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Haase MV; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Lewis AJ; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • McCleary S; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Mitchell DJ; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Moore SM; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Parr N; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Robb OJ; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Smithers N; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Soden PE; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Suckling CJ; Department of Pure & Applied Chemistry, University of Strathclyde, Glasgow, G1 1XL, U.K.
  • Taylor S; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Walker AL; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Watson RJ; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
  • Prinjha RK; GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
J Med Chem ; 64(16): 12200-12227, 2021 08 26.
Article in En | MEDLINE | ID: mdl-34387088
ABSTRACT
The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the in vivo tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Arthritis / Quinolines / Transcription Factors / Nuclear Proteins / Imidazoles / Anti-Inflammatory Agents Limits: Animals Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2021 Document type: Article Affiliation country: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Arthritis / Quinolines / Transcription Factors / Nuclear Proteins / Imidazoles / Anti-Inflammatory Agents Limits: Animals Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2021 Document type: Article Affiliation country: United kingdom