Development of radamide analogs as Grp94 inhibitors |
| |
| Institution: | 1. Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05, Hradec Králové, Czech Republic;2. MTA-ELTE Research Group of Peptide Chemistry, Eötvös Loránd Research Network (ELKH), Institute of Chemistry, Eötvös Loránd University, Pázmány Péter Sétány 1/A, Budapest, H-1117, P.O. Box 32, 1518, Budapest 112, Hungary;3. Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 702 00, Ostrava, Czech Republic;4. Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina CH-1, Ilkovi?ova 6, 842 15, Bratislava, Slovakia;1. Department of Nuclear Medicine and Molecular Imaging, Ajou University School of Medicine, Suwon, Republic of Korea;2. Department of Pathology, Ajou University School of Medicine, Suwon, Republic of Korea;3. Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea;4. Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea;5. Department of Radiology, Ajou University School of Medicine, Suwon, Republic of Korea;1. Sorbonne universités, UPMC université Paris 06, GRC 01, GREEN, Group of Clinical Research in Neuro-Urology, 75005 Paris, France;2. AP–HP, hôpital Tenon, service de neuro-urologie, 75020 Paris, France |
| |
| 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 (Kd = 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. |
| |
| Keywords: | Hsp90 Grp94 |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
