snx-2112 and Neoplasms

Hsp90 is one of the most important chaperones involved in regulating the maturation of more than 300 client proteins, many of which are closely associated with refractory diseases, including cancer, neurodegenerative diseases, and viral infections. Clinical Hsp90 inhibitors bind to the ATP pocket in the N-terminal domain of Hsp90 and subsequently suppress the ATPase activity of Hsp90. Recently, with the increased understanding of the discrepancies in the isoforms of Hsp90 and the modes of Hsp90-co-chaperone-client complex interactions, some new strategies for Hsp90 inhibition have emerged. Novel Hsp90 inhibitors that offer selective suppression of Hsp90 isoforms or specific disruption of Hsp90-co-chaperone protein-protein interactions are expected to show with satisfactory efficacy and safety profiles. This review summarizes the recent progress in Hsp90 inhibitors. Additionally, Hsp90 inhibitory strategies are emphasized in this review.

Topics: Animals; Antineoplastic Agents; Autoimmune Diseases; Benzoquinones; Forecasting; HSP90 Heat-Shock Proteins; Humans; Immunosuppressive Agents; Lactams, Macrocyclic; Molecular Chaperones; Neoplasms; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary

Orally administered SNX-5422, a novel, selective prodrug of the Heat shock protein 90 (Hsp90) inhibitor SNX-2112, was investigated in two sequential phase I studies to determine the safety, maximum tolerated doses (MTDs) and pharmacokinetic profile of SNX-5422.. Using a dose-escalation design, 3-6 adults with advanced solid tumours received SNX-5422 every-other-day (QOD) or once-daily (QD) 3weeks on/1week off or QD continuously, with disease assessments every 8 weeks. Single-dose and steady-state pharmacokinetic parameters of SNX-2112 were determined.. In total, 56 patients were enrolled: QOD 3 weeks on/1 week off, n=36; QD 3weeks on/1 week off, n=17; QD continuous, n=3. Doses ranged from 4 to 133mg/m(2) QOD and 50 to 89 mg/m(2) QD. The MTDs were defined as 100mg/m(2) QOD and 67 mg/m(2) QD, respectively, with diarrhoea being dose-limiting on both 3 weeks on/1 week off schedules. Overall, treatment-related adverse events were mainly low grade, including diarrhoea (64%), nausea (39%), fatigue (28%), and vomiting (28%). Reversible grade 1-3 nyctalopia (night blindness) was reported by four patients (dose: 50-89mg/m(2) QD; 100mg/m(2) QOD). Exposure was generally linear, though greater than dose-proportional. Of 32 evaluable patients on QOD dosing, there was one durable complete response (prostate cancer), one confirmed (HER2+breast cancer) and one unconfirmed partial response (adrenal gland cancer). Three patients (QOD schedule) had stable disease for ⩾ 6 months.. The dose and schedule recommended for further study with SNX-5422 is 100mg/m(2) QOD 3 weeks on/1 week off based on improved tolerability and preliminary evidence of clinical activity.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Benzamides; Biological Availability; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Glycine; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; Indazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Prodrugs; Vision Disorders

The 90 kD heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding of select proteins, many of which are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials for the treatment of cancer, all of which bind the Hsp90 N-terminus and exhibit

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Gene Silencing; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; Models, Molecular; Molecular Conformation; Neoplasms; Protein Folding; Small Molecule Libraries; Structure-Activity Relationship; Substrate Specificity; Urinary Bladder Neoplasms

Conventional therapeutic approaches to treat malignant tumors such as surgery, chemotherapy, or radiotherapy often lead to poor therapeutic results, great pain, economic burden, and risk of recurrence and may even increase the difficulty in treating the patient. Long-term drug administration and systemic drug delivery for cancer chemotherapy would be accompanied by drug resistance or unpredictable side effects. Thus, the use of photothermal therapy, a relatively rapid tumor elimination technique that regulates autophagy and exerts an antitumor effect, represents a novel solution to these problems. Heat shock protein 90 (HSP90), a protein that reduces photothermal or hypothermic efficacy, is closely related to AKT (protein kinase B) and autophagy. Therefore, it was hypothesized that autophagy could be controlled to eliminate tumors by combining exogenous light with a selective HSP90 inhibitor, for example, SNX-2112. In this study, an efficient tumor-killing strategy using graphene oxide loaded with SNX-2112 and folic acid for ultrafast low-temperature photothermal therapy (LTPTT) is reported. A unique mechanism that achieves remarkable therapeutic performance was discovered, where overactivated autophagy induced by ultrafast LTPTT led to direct apoptosis of tumors and enabled functional recovery of T cells to promote natural immunity for actively participating in the attack against tumors. This LTPTT approach resulted in residual tumor cells being rendered in an "injured" state, opening up the possibility of concurrent antitumor and antirecurrence treatment.

Topics: Animals; Antineoplastic Agents; Autophagy; Cell Line, Tumor; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; Male; Mice, Inbred BALB C; Neoplasms; Photochemotherapy; Proto-Oncogene Proteins c-akt; T-Lymphocytes; Temperature

The anti-HER2 antibody Trastuzumab (Herceptin) has been proven to be effective in the treatment of HER2-overexpressing breast cancer; resistance, however, invariably emerges in metastatic tumors. The expression of p95-HER2, a form of HER2 with a truncated extracellular domain that lacks the Trastuzumab binding epitope, has been implicated as a mechanism of resistance to the antibody. We utilized an in vivo tumor model that overexpresses p95-HER2 and showed it to be resistant to the signaling and antitumor effects of Trastuzumab. We find that both full-length and p95-HER2 interact with the HSP90 chaperone protein and are degraded in tumor cells exposed to HSP90 inhibitors in tissue culture and in vivo. Loss of expression of p95-HER2 is accompanied by downregulation of the phosphoinositide-3 kinase/AKT and extracellular signal-regulated kinase signaling pathways and inhibition of cell proliferation. Chronic administration of HSP90 inhibitors in vivo results in sustained loss of HER2 and p95-HER2 expression and inhibition of AKT activation, together with induction of apoptosis and complete inhibition of tumor growth in Trastuzumab-resistant, p95-HER2-overexpressing models. Thus, p95-HER2 is an HSP90 client protein, the expression and function of which can be effectively suppressed in vivo by HSP90 inhibitors. HSP90 inhibition is therefore a potentially effective therapeutic strategy for p95-HER2-mediated Trastuzumab-resistant breast cancer.

Topics: 3T3 Cells; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Binding Sites; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Heterocyclic Compounds, 4 or More Rings; HSP90 Heat-Shock Proteins; Humans; Immunoblotting; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Binding; Proto-Oncogene Proteins c-akt; Receptor, ErbB-2; Signal Transduction; Trastuzumab; Tumor Burden; Xenograft Model Antitumor Assays