Targeting the Hsp90 C-terminal domain to induce allosteric inhibition and selective client downregulation.

ABSTRACT:

Background

Inhibition of Hsp90 is desirable due to potential downregulation of oncogenic clients. Early generation inhibitors bind to the N-terminal domain (NTD) but C-terminal domain (CTD) inhibitors are a promising class because they do not induce a heat shock response. Here we present a new structural class of CTD binding molecules with a unique allosteric inhibition mechanism.

Methods

A hit molecule, NSC145366, and structurally similar probes were assessed for inhibition of Hsp90 activities. A ligand-binding model was proposed indicating a novel Hsp90 CTD binding site. Client protein downregulation was also determined.

Results

NSC145366 interacts with the Hsp90 CTD and has anti-proliferative activity in tumor cell lines (GI₅₀=0.2-1.9μM). NSC145366 incre

SUBMITTER: Goode KM 

PROVIDER: S-EPMC6453127 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature