title: Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90.
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.
authors.affiliation: Exelixis, Inc., 220 East Grand Ave., South San Francisco, CA 94080, USA.
authors.forename: Joerg
authors.initials: J
authors.lastname: Bussenius
authors.forename: Charles M
authors.initials: CM
authors.lastname: Blazey
authors.forename: Naing
authors.initials: N
authors.lastname: Aay
authors.forename: Neel K
authors.initials: NK
authors.lastname: Anand
authors.forename: Arlyn
authors.initials: A
authors.lastname: Arcalas
authors.forename: TaeGon
authors.initials: T
authors.lastname: Baik
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Bowles
authors.forename: Chris A
authors.initials: CA
authors.lastname: Buhr
authors.forename: Simona
authors.initials: S
authors.lastname: Costanzo
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Curtis
authors.forename: Steven C
authors.initials: SC
authors.lastname: DeFina
authors.forename: Larisa
authors.initials: L
authors.lastname: Dubenko
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Heuer
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Christopher
authors.initials: C
authors.lastname: Jaeger
authors.forename: Anagha
authors.initials: A
authors.lastname: Joshi
authors.forename: Abigail R
authors.initials: AR
authors.lastname: Kennedy
authors.forename: Angie I
authors.initials: AI
authors.lastname: Kim
authors.forename: Katherine
authors.initials: K
authors.lastname: Lara
authors.forename: Jae
authors.initials: J
authors.lastname: Lee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Li
authors.forename: Julie C
authors.initials: JC
authors.lastname: Lougheed
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Ma
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: Jean-Claire L
authors.initials: JC
authors.lastname: Manalo
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Martini
authors.forename: Garth
authors.initials: G
authors.lastname: McGrath
authors.forename: Monique
authors.initials: M
authors.lastname: Nicoll
authors.forename: John M
authors.initials: JM
authors.lastname: Nuss
authors.forename: Michael
authors.initials: M
authors.lastname: Pack
authors.forename: Csaba J
authors.initials: CJ
authors.lastname: Peto
authors.forename: Tsze H
authors.initials: TH
authors.lastname: Tsang
authors.forename: Longcheng
authors.initials: L
authors.lastname: Wang
authors.forename: Scott W
authors.initials: SW
authors.lastname: Womble
authors.forename: Michael
authors.initials: M
authors.lastname: Yakes
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Rice
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010795:Phthalic Acids / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D018841:HSP90 Heat-Shock Proteins; D010795:Phthalic Acids; C559121:XL 888