2. Academic Validation
  3. Tricyclic series of heat shock protein 90 (Hsp90) inhibitors part I: discovery of tricyclic imidazo[4,5-c]pyridines as potent inhibitors of the Hsp90 molecular chaperone

Tricyclic series of heat shock protein 90 (Hsp90) inhibitors part I: discovery of tricyclic imidazo[4,5-c]pyridines as potent inhibitors of the Hsp90 molecular chaperone

  • J Med Chem. 2011 Oct 27;54(20):7206-19. doi: 10.1021/jm200784m.
François Vallée 1,  Chantal Carrez,  Fabienne Pilorge,  Alain Dupuy,  Annick Parent,  Luc Bertin,  Fabienne Thompson,  Paul Ferrari,  Florence Fassy,  Annabelle Lamberton,  Anne Thomas,  Rosalia Arrebola,  Stéphane Guerif,  Alexandre Rohaut,  Victor Certal,  Jean-Marie Ruxer,  Thierry Gouyon,  Cécile Delorme,  Alain Jouanen,  Jacques Dumas,  Claudine Grépin,  Cécile Combeau,  Hélène Goulaouic,  Norbert Dereu,  Vincent Mikol,  Patrick Mailliet,  Hervé Minoux
Affiliations

Affiliation

  • 1 Sanofi-Aventis Research and Development, 13 Quai Jules Guesde, BP 14, 94400 Vitry-sur-Seine, France.
PMID: 21972823 DOI: 10.1021/jm200784m
Abstract

A novel class of heat shock protein 90 (HSP90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 μM on Hsp82, the yeast homologue of HSP90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other HSP90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.

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