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

Lead optimization of tropane-derived HTS hits driven by traditional SAR and X-ray crystallography led to the identification of clinical candidate 12i (XL888). With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (17), p.5396-5404
Hauptverfasser:	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.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animal models Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Azabicyclo Compounds - chemistry Azabicyclo Compounds - pharmacokinetics Azabicyclo Compounds - pharmacology Azabicyclo Compounds - therapeutic use Biological and medical sciences Cancer Cell Line, Tumor Cell Proliferation - drug effects Crystallography, X-Ray Development Drug Discovery General pharmacology HSP90 HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - metabolism Hsp90 protein Humans Inhibitor Medical sciences Mice Models, Molecular Neoplasms - drug therapy Neoplasms - metabolism Neoplasms - pathology Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Phthalic Acids - chemistry Phthalic Acids - pharmacokinetics Phthalic Acids - pharmacology Phthalic Acids - therapeutic use protein content Regression analysis remission Tropane Tumors Xenografts XL888
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Zusammenfassung:	Lead optimization of tropane-derived HTS hits driven by traditional SAR and X-ray crystallography led to the identification of clinical candidate 12i (XL888). 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.07.052