HSP90 Inhibitor

Tanespimycin (17-AAG) is a potent HSP90 inhibitor with an IC₅₀ of 5 nM, having a 100-fold higher binding affinity for tumour cell derived HSP90 than normal cell derived HSP90. Tanespimycin depletes cellular STK38/NDR1 and reduces STK38 kinase activity. Tanespimycin also downregulates the stk38 gene expression.

Geldanamycin is a Hsp90 inhibitor with antimicrobial activity against many Gram-positive and some Gram-negative bacteria. Geldanamycin has anti-influenza virus H5N1 activities.

Ganetespib (STA-9090) is a heat shock protein 90 (HSP90) inhibitor which exhibits potent cytotoxicity in a wide variety of hematological and solid tumor cell lines. Ganetespib has antiangiogenic effects in colorectal cancer mediated through inhibition of HIF-1α and STAT3.

SNX-7081 is an Hsp90 inhibitor with K_i and IC₅₀ values of 26 nM and 44 nM, respectively. SNX-7081 blocks the nuclear translocation of NF-κB, inhibits the production of pro-inflammatory cytokines, attenuates the ERK/JNK and PDGF signaling pathways, and suppresses LPS (HY-D1056)-induced nitric oxide production. SNX-7081 inhibits DNA repair, induces G₂/M cell cycle arrest, and triggers apoptosis via downregulation of MYC/nucleolin and activation of Fas. SNX-7081 can be used in research related to rheumatoid arthritis and cancer.

KUNG94 is a selective Grp94/HSP90B inhibitor (IC₅₀=8 nM). By inhibiting the chaperone function of Grp94, KUNG94 reduces the maturation and cell surface trafficking of its specific client proteins. KUNG94 can be used for studies on Grp94-related biological mechanisms, as well as diseases including cancer and primary open-angle glaucoma.

VWK147 is a second-generation HSP90 C-terminal domain (CTD) inhibitor. VWK147 targets the CTD dimerization interface, prevents HSP90 CTD dimerization, disrupts co-chaperone PPID binding to HSP90 CTD, and inhibits HSP90 chaperone function dependent on dimerization. VWK147 reduces protein levels of HSP90 client proteins ULK1, RIPK1, and CDK4 without inducing a heat shock response. VWK147 induces cell death, including apoptosis, in Cisplatin (HY-17394)-sensitive and -resistant urothelial carcinoma cells. VWK147 induces LC3-II accumulation, inhibits autophagosome-lysosome fusion to block canonical autophagy, and induces non-canonical LC3 lipidation independent of ULK1 and PIK3C3 complexes. VWK147 can be used for the research of urothelial carcinoma.

Luminespib (VER-52296) is a potent HSP90 inhibitor with IC₅₀s of 7.8 and 21 nM for HSP90α and HSP90β, respectively.

Gamitrinib TPP hexafluorophosphate is a Gamitrinib (GA) mitochondrial matrix inhibitor. Gamitrinib TPP hexafluorophosphate is a mitochondrial targeted HSP90 inhibitor with anti-cancer activity.

Pimitespib (TAS-116) is an oral bioavailable, ATP-competitive, highly specific HSP90α/HSP90β inhibitor (K_is of 34.7 nM and 21.3 nM, respectively) without inhibiting other HSP90 family proteins such as GRP94. Pimitespib demonstrates less ocular toxicity.

Onalespib (AT13387) is a potent and cross the blood-brain barrier heat-shock-protein-90 (Hsp90) inhibitor. Onalespib inhibits the proliferation, survival and migration. Onalespib decreases the expression of EGFR, p-EGFR, AKT, P-AKT, ERK1/2, P-ERK1/2, S6, P-S6 protein. Onalespib shows antitumor activity. Onalespib has the potential for the research of non-small cell lung cancer (NSCLC).

BIIB021 (CNF2024) is an orally active, fully synthetic inhibitor of HSP90 with a K_i and an EC₅₀ of 1.7 nM and 38 nM, respectively.

Alvespimycin (17-DMAG) is a potent inhibitor of Hsp90, binding to Hsp90 with an EC₅₀ of 62 nM.

Zelavespib (PU-H71) is a potent Hsp90 inhibitor, with an IC₅₀ of 51 nM in MDA-MB-468 cells.

PU-WS13 is a selective Grp94 inhibitor, with an EC₅₀ of 0.22 μM.

Alvespimycin hydrochloride (17-DMAG hydrochloride; KOS-1022; BMS 826476) is a potent inhibitor of Hsp90, binding to Hsp90 with EC₅₀ of 62±29 nM.

NVP-HSP990 is a potent, selective and orally active Hsp90 inhibitor, with IC₅₀ values of 0.6, 0.8, and 8.5 nM for Hsp90α, Hsp90β, and Grp94, respectively.

Radicicol is an inhibitor of Hsp90 with an IC₅₀ value < 1 μM, and leads to proteasomal degradation. Radicicol exhibits inhibition on PDK with IC₅₀s of 230 μM (PDK1) and 400 μM (PDK3). Radicicol is an antifungal and antimalarial antibiotic, impairs mitochondrial replication by targeting P. falciparum topoisomerase VIB. Radicicol is also an inhibitor of fat mass and obesity-associated protein (FTO), with an IC₅₀ value of 16.04 μM.

XL888 is a potent and orally active HSP90 inhibitor with an IC₅₀ value of 24 nM. XL888 shows anti-proliferation activity and induces Apoptosis. XL888 shows anti-tumor activity.

SNX-2112 (PF 04928473) is an orally active Hsp90 inhibitor, with a K_d of 16 nM for Hsp90 and IC₅₀s of 30 nM, 30 nM for Hsp90 α and Hsp90 β, also induces Her-2 degradation, and inhibits Grp94 and Trap-1, with IC₅₀s of 10 nM, 4.275 μM and 0.862 μM, respectively. SNX-2112 (PF 04928473) binds Hsp90 isoforms Hsp90α, Hsp90β and Hsp90b1/Grp94 with K_ds of 4 nM, 6 nM and 484 nM, respectively.

Grp94 Inhibitor-1 is a potent, selective Grp94 inhibitor with an IC₅₀ value of 2 nM, and over 1000-fold selectivity to Grp94 against Hsp90α.