HSP Inhibitor

Displurigen (NSC375009) disrupts human embryonic stem cell pluripotency by targeting HSPA8. Displurigen inhibits ATPase activity of HSP70 (IC₅₀ = 225 μM).

Wighteone (6-Isopentenylgenistein; Erythrinin B) is a prenylated isoflavone that acts as a HSP90/EGFR^L858R/T790M inhibitor and antifungal agent. Wighteone reduces the expression level of HSP90, blocks EGF-induced phosphorylation of EGFR, and thereby inhibits the downstream ERK and AKT signaling pathways. Wighteone induces cell cycle redistribution, inhibits proliferation and triggers apoptosis in cancer cells. Wighteone can be isolated from Erythrina suberosa, and can also be induced to synthesize in Lotus japonicus under specific conditions. Wighteone can be used to study HER2-positive breast cancer, leukemia, non-small cell lung cancer with EGFR^L858R/T790M mutation, and fungal infections.

YK5 is a potent and selective Hsp70 inhibitor. YK5 selectively and tightly binds to the cytosolic Hsp70s in cancer cells. YK5 has biological activity partly by interfering with the formation of active oncogenic Hsp70/Hsp90/client protein complexes.

Hsp90-IN-37 (Z-2) is a heat shock protein 90 (Hsp90) inhibitor that inhibits Hsp90 enzymatic activity by 69%. Hsp90-IN-37 has antitumor activity.

TRAP1-IN-1 (compound 35) is a potent and selective inhibitor of TRAP1，a mitochondrial isoform of Hsp90. TRAP1-IN-1 has >250-fold TRAP1 selectivity over Grp94，and disrupts TRAP1 tetramer stability，induces TRAP1 client protein degradation. TRAP1-IN-1 also inhibits mitochondrial complex I of oxidative phosphorylation OXPHOS，disrupts the mitochondrial membrane potential，and enhances glycolysis metabolism.

Falcarinol (Panaxynol) is a natural, orally active Hsp90 inhibitor targeting both the N-terminal and C-terminal of Hsp90 with limited toxicities. Falcarinol (Panaxynol) induces apoptosis. Falcarinol is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.

PU-H54, a Grp94-selective inhibitor, can be used for the research of breast cancer. Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90β, Grp94 and Trap-1, has important roles in malignancy. PU-H54 is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.

SMTIN-T140 (compound 6a) is a potent TRAP1 (tumor-necrosis-factor-receptor associated protein 1) inhibitor, with an IC₅₀ of 1.646 μM. SMTIN-T140 shows anticancer activity. SMTIN-T140 leads to mitochondrial dysfunction, increases mitochondrial ROS production and activates AMPK. SMTIN-T140 potently suppressed tumor growth without any noticeable in vivo toxicity in a mouse model xenografted with PC3 prostate cancer cells.

PDK-IN-1 (compound 7o) is a pyruvate dehydrogenase kinase (PDK) inhibitor. PDK-IN-1 shows IC₅₀ values of 0.03 and 0.1 μM for PDK1 and HSP90, respectively. PDK-IN-1 targets PDH/PDK axis thus reducing efficiently the tumor mass.

Conglobatin (FW-04-806), a macrolide dilactone, is isolated from the culture of Streptomyces conglobatus. Conglobatin is an orally active Hsp90 inhibitor. Conglobatin can bind to the N-terminal domain of Hsp90 and disrupt Hsp90-Cdc37 complex formation. Conglobatin induces apoptosis in human breast cancer cells and esophageal squamous cell carcinoma cells, and exhibits antitumor activity in vivo.

Gedunin is a limonoid with anti-cancer, anti-viral, anti-inflammatory and insecticidal activities. Gedunin acts as a potent Hsp90 inhibitor and induces the degradation of Hsp90-dependent client proteins. Geduni may obstructs the entry of SARS-CoV-2 virus into human host cells and can be used for COVID-19 research.

MK2-IN-1 (compound 1) is a potent and selecitve MAPKAPK2 (MK2) inhibitor with an IC₅₀ of 0.11 uM for MK2 and an EC₅₀ of 0.35 uM for pHSP27. MK2-IN-1 impaires the phosphorylation level of serine residues in the Tfcp2l1 protein.

Gamendazole, an indazole carboxylic acid (ICA), is an orally active, selective HSP90AB1 (HSP90BETA) and EEF1A1 (eEF1A) inhibitor. Gamendazole binds to the C-terminal nucleotide binding pocket of HSP90 and cause downregulation of clients AKT1 and ERBB2, but stabilizes the HSP90 heterocomplex. Gamendazole specifically inhibits the actin bundling function of EEF1A1, but does not bind to the nucleotide docking pocket nor inhibits the ribosome charging or protein translation functions of EEF1A1. Gamendazole, an antispermatogenic compound with antifertility effects, has the potential for reversible non-hormonal male contraceptive agent research.

HEMTAC WEE1 degrader-1 is a HSP90-mediated targeting chimera (HEMTAC) degrader of WEE1 (HSP90 enzyme inhibitory activity is IC₅₀: 16.76 nM). HEMTAC WEE1 degrader-1 promotes the ubiquitination and degradation of WEE1. HEMTAC WEE1 degrader-1 blocks the G2/M cell cycle. HEMTAC WEE1 degrader-1 has anticancer activity in acute myeloid leukemia (AML) patient-derived xenograft (PDX) models. HEMTAC WEE1 degrader-1 can be used in AML research. (Pink: HSP90 binder; Blue: WEE1 ligand; Black: linker).

SEW84 is an inhibitor of Aha1-stimulated Hsp90 (ASH) ATPase activity. SEW84 inhibits Aha1-stimulated Hsp90 (ASH) activity with an IC₅₀ value of 0.3 μM. SEW84 can be used in the study of protein deposition diseases.

CH5138303 is a potent and orally active Hsp90 inhibitor. CH5138303 shows high binding affinity for N-terminal Hsp90α, with K_d of 0.52 nM. CH5138303 shows potent anti-proliferative activity against human cancer cell lines (HCT116 and NCI-N87), with IC₅₀ values of 0.098 and 0.066 μM, respectively. CH5138303 shows high oral bioavailability in mice (F=44.0%). CH5138303 shows potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model.

AP-4-139B is a blood-brain barrier-permeable HSP70 inhibitor with a IC₅₀ of 180 nM against hHSP70. AP-4-139B binds directly to HSP70 and inhibits its ATPase activity. AP-4-139B promotes Autophagy by increasing the phosphorylation of Beclin-1. AP-4-139B exerts antitumor effects in preclinical models of colorectal cancer and pancreatic ductal adenocarcinoma.

HSP90-IN-22 (Compound 35) is an Hsp90 inhibitor with antiproliferative properties on cells with IC₅₀ values of 3.65 μM for MCF7 breast cancer cells and 2.71 μM for SKBr3 breast cancer cells, respectively.

HS-27, a fluorescently-tethered Hsp90 inhibitor, assays surface Hsp90 expression on intact tissue specimens. HS-27 is made up of the core elements of SNX-5422, an Hsp90 inhibitor, tethered via a PEG linker to a fluorescein derivative (fluorescein isothiocyanate or FITC), that binds to ectopically expressed Hsp90. HS-27 has potential use in a see-and-treat paradigm in breast cancer.

HSP70-IN-9 is an Hsp70 inhibitor that induces caspase-3,7 activation with an IC₅₀ of 25.2 μM. HSP70-IN-9 reversibly binds to the allosteric pocket of the N-terminal domain, disrupts the Hsp70-HOP-Hsp90 mega-complex, and inhibits client protein refolding, thereby inducing apoptosis and degradation of Hsp90-Hsp70 tumor client proteins, ultimately inhibiting cancer cell growth. HSP70-IN-9 can be used for research on breast cancer, pancreatic cancer, and acute myeloid leukemia.