Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90

  • Bioorg Med Chem Lett. 2012 Sep 1;22(17):5396-404. doi: 10.1016/j.bmcl.2012.07.052.
Joerg Bussenius  1 ,  Charles M Blazey ,  Naing Aay ,  Neel K Anand ,  Arlyn Arcalas ,  TaeGon Baik ,  Owen J Bowles ,  Chris A Buhr ,  Simona Costanzo ,  Jeffrey K Curtis ,  Steven C DeFina ,  Larisa Dubenko ,  Timothy S Heuer ,  Ping Huang ,  Christopher Jaeger ,  Anagha Joshi ,  Abigail R Kennedy ,  Angie I Kim ,  Katherine Lara ,  Jae Lee ,  Jonathan Li ,  Julie C Lougheed ,  Sunghoon Ma ,  Shiva Malek ,  Jean-Claire L Manalo ,  Jean-Francois Martini ,  Garth McGrath ,  Monique Nicoll ,  John M Nuss ,  Michael Pack ,  Csaba J Peto ,  Tsze H Tsang ,  Longcheng Wang ,  Scott W Womble ,  Michael Yakes ,  Wentao Zhang ,  Kenneth D Rice
Affiliations
  • 1. Exelixis, Inc., 220 East Grand Ave., South San Francisco, CA 94080, USA.
PMID: 22877636 DOI: 10.1016/j.bmcl.2012.07.052
Abstract

With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.