4-Amino derivatives of the Hsp90 inhibitor CCT018159

  • Bioorg Med Chem Lett. 2006 May 1;16(9):2543-8. doi: 10.1016/j.bmcl.2006.01.099.
Xavier Barril  1 ,  Mandy C Beswick ,  Adam Collier ,  Martin J Drysdale ,  Brian W Dymock ,  Alexandra Fink ,  Kate Grant ,  Robert Howes ,  Allan M Jordan ,  Andrew Massey ,  Allan Surgenor ,  Joanne Wayne ,  Paul Workman ,  Lisa Wright
Affiliations
  • 1. Vernalis Ltd, Granta Park, Cambridge CB1 6GB, UK.
PMID: 16480864 DOI: 10.1016/j.bmcl.2006.01.099
Abstract

Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based HSP90 Inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human HSP90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.