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

Biochimica Et Biophysica Acta. General Subjects
Kourtney M GoodeTony R Hazbun

Abstract

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. 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. NSC145366 interacts with the Hsp90 CTD and has anti-proliferative activity in tumor cell lines (GI50=0.2-1.9μM). NSC145366 increases Hsp90 oligomerization resulting in allosteric inhibition of NTD ATPase activity (IC50=119μM) but does not compete with NTD or CTD-ATP binding. Treatment of LNCaP prostate tumor cells resulted in selective client protein downregulation including AR and BRCA1 but without a heat shock response. Analogs had similar potencies in ATPase and chaperone activity assays and variable effects on oligomerization. In silico modeling predicted a binding site at the CTD dimer interface distinct from the nucleotid...Continue Reading

Citations

Jan 18, 2018·Antimicrobial Agents and Chemotherapy·Dora PosfaiEmily R Derbyshire
Mar 6, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Dongrong ZhuJianguang Luo
Aug 29, 2021·Pharmaceutics·Jaka DernovšekTihomir Tomašič
Jun 24, 2021·Molecular Cancer Therapeutics·David E DurrantDeborah K Morrison

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