Discovery and Development of a Selective Inhibitor of the ER Resident Chaperone Grp78

Andrew J. Ambrose, Jared Sivinski, Christopher J. Zerio, Xiaoyi Zhu, Jack Godek, Vlad K. Kumirov, Teresa Coma Brujas, Joan Torra Garcia, Anandhan Annadurai, Cody J. Schmidlin, Alyssa Werner, Taoda Shi, Reza Beheshti Zavareh, Luke Lairson, Donna D. Zhang, Eli Chapman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


A recent study illustrated that a fluorescence polarization assay can be used to identify substrate-competitive Hsp70 inhibitors that can be isoform-selective. Herein, we use that assay in a moderate-throughput screen and report the discovery of a druglike amino-acid-based inhibitor with reasonable specificity for the endoplasmic reticular Hsp70, Grp78. Using traditional medicinal chemistry approaches, the potency and selectivity were further optimized through structure-activity relationship (SAR) studies in parallel assays for six of the human Hsp70 isoforms. The top compounds were all tested against a panel of cancer cell lines and disappointingly showed little effect. The top-performing compound, 8, was retested using a series of endoplasmic reticulum (ER) stress-inducing agents and found to synergize with these agents. Finally, 8 was tested in a spheroid tumor model and found to be more potent than in two-dimensional models. The optimized Grp78 inhibitors are the first reported isoform-selective small-molecule-competitive inhibitors of an Hsp70-substrate interaction.

Original languageEnglish (US)
Pages (from-to)677-694
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - Jan 12 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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