title: Development of radamide analogs as Grp94 inhibitors.
abstract: Hsp90 isoform-selective inhibition is highly desired as it can potentially avoid the toxic side-effects of pan-inhibition. The current study developed selective inhibitors of one such isoform, Grp94, predicated on the chimeric and pan-Hsp90 inhibitor, radamide (RDA). Replacement of the quinone moiety of RDA with a phenyl ring (2) was found to be better suited for Grp94 inhibition as it can fully interact with a unique hydrophobic pocket present in Grp94. An extensive SAR for this scaffold showed that substitutions at the 2- and 4-positions (8 and 27, respectively) manifested excellent Grp94 affinity and selectivity. Introduction of heteroatoms into the ring also proved beneficial, with a 2-pyridine derivative (38) exhibiting the highest Grp94 affinity (K(d)=820 nM). Subsequent cell-based assays showed that these Grp94 inhibitors inhibit migration of the metastatic breast cancer cell line, MDA-MB-231, as well as exhibit an anti-proliferative affect against the multiple myeloma cell line, RPMI 8226.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Muth
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors.forename: Vincent
authors.initials: V
authors.lastname: Crowley
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors.forename: Anuj
authors.initials: A
authors.lastname: Khandelwal
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors.forename: Sanket
authors.initials: S
authors.lastname: Mishra
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors.forename: Jinbo
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hall
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Malott 4070, Lawrence, KS 66045-7563, United States. Electronic address: bblagg@ku.edu.
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D000083:Acetanilides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005454:Fluorescence Polarization; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000083:Acetanilides; D001565:Benzoates; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; C018551:glucose-regulated proteins; C540759:radamide
keywords: Grp94; Hsp90