2. Academic Validation
  3. Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors

Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors

  • J Med Chem. 2021 Mar 25;64(6):3249-3281. doi: 10.1021/acs.jmedchem.0c02156.
Helen E Aylott 1,  Stephen J Atkinson 1,  Paul Bamborough 2,  Anna Bassil 1,  Chun-Wa Chung 2,  Laurie Gordon 2,  Paola Grandi 3,  James R J Gray 4,  Lee A Harrison 1,  Thomas G Hayhow 1,  Cassie Messenger 2,  Darren Mitchell 1,  Alexander Phillipou 2,  Alex Preston 1,  Rab K Prinjha 1,  Francesco Rianjongdee 1,  Inmaculada Rioja 1,  Jonathan T Seal 1,  Ian D Wall 2,  Robert J Watson 1,  James M Woolven 2,  Emmanuel H Demont 1
Affiliations

Affiliations

  • 1 Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 2 Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 3 IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstr. 1, Heidelberg 69117, Germany.
  • 4 Quantitative Pharmacology, Immunoinflammation Therapy Area Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K.
PMID: 33662213 DOI: 10.1021/acs.jmedchem.0c02156
Abstract

A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 (3) and GSK620 (5). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds 28 (GSK452), 39 (GSK737), and 36 (GSK217).

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