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

Autor:	Sunghoon Ma, Julie Lougheed, Christopher Jaeger, Scott W. Womble, Jean-Claire Limun Manalo, Chris A. Buhr, Longcheng Wang, Wentao Zhang, Kenneth D. Rice, Steven Charles Defina, Abigail R. Kennedy, Timothy S. Heuer, Michael Yakes, Neel Kumar Anand, Tae-Gon Baik, Curtis Jeff Kimo, Joerg Bussenius, Angie I. Kim, Jonathan C. Li, Michael Pack, Csaba J. Peto, Monique Nicoll, Naing Aay, Simona Costanzo, Jae Lee, Garth Joseph Mcgrath, Charles M. Blazey, Tsze H. Tsang, Shiva Malek, Anagha Abhijit Joshi, Arlyn Arcalas, Ping Huang, Larisa Dubenko, Jean-Francois Martini, Katherine Lara, John M. Nuss, Owen Joseph Bowles
Rok vydání:	2012
Předmět:	Models Molecular Clinical Biochemistry Phthalic Acids Pharmaceutical Science Antineoplastic Agents Pharmacology Crystallography X-Ray Biochemistry Protein content Mice chemistry.chemical_compound Mouse xenograft In vivo Cell Line Tumor Neoplasms Drug Discovery Tumor regression Animals Humans HSP90 Heat-Shock Proteins Molecular Biology Cell Proliferation biology Chemistry Drug discovery Organic Chemistry Tropane Hsp90 Small molecule biology.protein Molecular Medicine Azabicyclo Compounds
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 22:5396-5404
ISSN:	0960-894X
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bd3657e6e173629f0f09489df1637838 https://doi.org/10.1016/j.bmcl.2012.07.052 Zobrazit plný text záznamu Full Text from ScienceDirect