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

Joerg Bussenius, 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

Bioorganic & Medicinal Chemistry Letters 2012 September 2

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.

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