Development of radamide analogs as Grp94 inhibitors

作者：Muth Aaron; Crowley Vincent; Khandelwal Anuj; Mishra Sanket; Zhao Jinbo; Hall Jessica; Blagg Brian S J^*

来源：Bioorganic & Medicinal Chemistry, 2014, 22(15): 4083-4098.

DOI：10.1016/j.bmc.2014.05.075

• Hsp90
• Grp94

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.

• 出版日期2014-8-1