Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90
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.
Bussenius, Joerg,Blazey, Charles M.,Aay, Naing,Anand, Neel K.,Arcalas, Arlyn,Baik, Taegon,Bowles, Owen J.,Buhr, Chris A.,Costanzo, Simona,Curtis, Jeffrey K.,Defina, Steven C.,Dubenko, Larisa,Heuer, Timothy S.,Huang, Ping,Jaeger, Christopher,Joshi, Anagha,Kennedy, Abigail R.,Kim, Angie I.,Lara, Katherine,Lee, Jae,Li, Jonathan,Lougheed, Julie C.,Ma, Sunghoon,Malek, Shiva,Manalo, Jean-Claire L.,Martini, Jean-Francois,McGrath, Garth,Nicoll, Monique,Nuss, John M.,Pack, Michael,Peto, Csaba J.,Tsang, Tsze H.,Wang, Longcheng,Womble, Scott W.,Yakes, Michael,Zhang, Wentao,Rice, Kenneth D.
p. 5396 - 5404
(2012/09/22)
TROPANE COMPOUNDS
A compound according to Formula I or II: (I) or (II) wherein R1, R1b, R2, L1, and L2 and L2b are as defined in the specification, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 413
(2009/05/30)
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