KU-177

KU-177 is a potent inhibitor of Hsp90 ATPase homologue 1 (Aha1), ablates Aha1-driven enhancement of Hsp90-dependent tau aggregation. KU-177 also disrupts Aha1/Hsp90 interactions (IC50=4.08 μM) without inhibition of Hsp90’s ATPase activity. KU-177 can be used for tauopathies research[1][2].

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> HSP

Signaling Pathways >> Cell Cycle/DNA Damage >> HSP

HSP90

KU-177 (50 μM; 48 h) hampers the proliferation of flow MRD-positive cells in both primary multiple myeloma (MM) and recurrent MM patient samples[1]. KU-177 (30 μM; 48 h) inhibits proteasome activity in AHSA1 WT/OE cells, PSMD2 WT/OE cells and ANBL6 WT/DR cells[1]. KU-177 abrogates the cellular proliferation and PI resistance induced by elevated AHSA1, and decreases the expression of CDK6 and PSMD2[1]. KU-177 (25 μM; 30 min; 37 ℃) inhibits recombinant P301L tau aggregation without inhibiting Hsp90 to refold luciferase[2]. KU-177 (10 μM; 24 h) exhibits the ability to disrupt interactions between Aha1 and Hsp90 in SH-SY5Y neuroblastoma cells and SK-BR-3 breast cancer cells, without significantly inhibition on Hsp90 client protein (Her2)[2]. Cell Proliferation Assay[1] Cell Line: ARP1 and H929 WT and AHSA1-OE cells Concentration: 1 nM-100 μM Incubation Time: 24, 48, 72 hours Result: Decreased multiple myeloma (MM) cell proliferation and PI resistance induced by AHSA1/HSP90 in vitro. Cell Proliferation Assay[2] Cell Line: SH-SY5Y neuroblastoma cells and Her2 overexpressing SK-BR-3 breast cancer cells Concentration: 10 μM Incubation Time: 24 hours Result: Didn’t induce the degradation of Hsp90 client proteins Her2 (in SK-BR-3 cells), Cdk6, or pAktS473 (in SHSY5Y cells), nor induced the expression of Hsp70, a marker of the heat shock response.

KU-177 (1 mg/kg; i.p.; twice a week; 4 weeks), inhibits tumor growth and extends the survival of 5TMM3VT MM mice without significant toxicity. KU-177 shows stronger efficacy in vivo, combined with Bortezomib (HY-10227) (1 mg/kg; i.p.)[1]. Animal Model: 5TMM3VT mouse model (6-8 weeks old, C57BL/KaLwrij mice)[1] Dosage: 1 mg/kg Administration: Intraperitoneal injection; twice a week; sacrificed mice with hindlimb weakness immediately, about 4-5 weeks Result: Inhibited the xenograft tumor growth of both ANBL6 WT/BTZ-DR cells. Didn’t induce histopathological abnormities or lesions in main organs including heart, liver, spleen, lung and kidney.

[1]. Gu C, et al. AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma. J Exp Clin Cancer Res. 2022 Jan 6;41(1):11. 

[2]. Keegan BM, et al. Synthesis and Evaluation of Small Molecule Disruptors of the Aha1/Hsp90 Complex for the Reduction of Tau Aggregation. ACS Med Chem Lett. 2022 Apr 15;13(5):827-832.