SNX-2112 / Esanex - LARVOL DELTA

NN-01-195, a novel conjugate of HSP90 and AURKA inhibitors, effectively targets solid tumors. (PubMed, Mol Cancer Ther) - "We developed NN-01-195 as a novel chimeric small molecule that combines an AURKA inhibitor related to TAS-119/VIC-1911 with an HSP90-binding moiety related to SNX2112, and evaluated its function. Further, in combination with an inhibitor of the G2/M checkpoint protein WEE1, NN-01-195 is more potent than VIC-1911 in limiting growth of xenograft tumors. These data support the exploration of NN-01-195 and improved analogs as promising new candidates for therapeutic evaluation."

Journal • Oncology • Solid Tumor • CDC37 • HSP90AA1

Novel furanone-based anticancer agents: Design, synthesis, Hsp90 inhibition, in vivo antitumor activity and pharmacokinetic studies. (PubMed, Eur J Med Chem) - "In a TNBC xenograft model, 13b significantly reduced tumor volume and weight with a better safety profile than 5-fluorouracil. Molecular docking studies showed that 13b binds within the Hsp90 ATP-binding pocket in a comparable pattern to the known inhibitors, SNX-2112 and GDM. These findings support 13b as a promising and well-tolerated Hsp90-targeted anticancer lead, especially for the treatment of breast cancer."

Journal • PK/PD data • Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC37 • CDK4 • EGFR • HER-2 • HSP90AA1

The Combination of HSP90 Inhibitors and Selumetinib Reinforces the Inhibitory Effects on Plexiform Neurofibromas. (PubMed, Cancers (Basel)) - " We demonstrated that combining selumetinib and SNX-2112 or retaspimycin can achieve better tumor inhibition with synergistic effects. The combination significantly delays the progression of mouse pNFs. The combination of selumetinib and HSP90i has significant synergistic effects, provides therapeutic inhibitor effects, and reduces the selumetinib dosage in combination."

Journal • Neurofibromatosis • Oncology • Pediatrics • Solid Tumor • Transplantation • CDC37 • NF1

ImmuProgML: machine learning-based dissection of cancer-immune dynamics during tumor progression to improve immunotherapy. (PubMed, J Transl Med) - "ImmuProgML offers a promising avenue for understanding the intricate relationship between tumors and the immune system, providing a machine learning framework for personalized cancer immunotherapy selections."

Biomarker • IO biomarker • Journal • Cognitive Disorders • Immunology • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CXCR4 • PRKCB

Tetrahydroindazolone-substituted Benzamide Compound W-H4 Induces Apoptosis and Autophagy of Acute Myeloid Leukemia Cells. (PubMed, Anticancer Res) - "W-H4 emerges as a potential Hsp90 inhibitor, providing novel therapeutic opportunities for the targeted treatment of acute myeloid leukemia."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • BCL2 • CDC37

Suppression of the HSP90-HIF1α pathway with SNX2112-encapsulated nano-micelles for effective triple-negative breast cancer photothermal combined photodynamic therapy. (PubMed, J Mater Chem B) - "Consequently, the combined therapy enhanced by inhibiting HSP90-HIF1α effectively suppresses tumor growth via synergistic effects, with high photothermal conversion and ROS productivity under mild temperature (42 °C). Furthermore, using SNX2112 improves the efficacy of the combined photothermal and photodynamic therapy, showing its eminent potential in TNBC treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDC37 • HIF1A • HSP90AA1

Multi-omic analyses reveal PTPN6's impact on tumor immunity across various cancers. (PubMed, Sci Rep) - "Drug sensitivity analysis identified specific drugs, including PAC-1, SNX-2112, BELINOSTAT, VORINOSTAT, TPCA-1, and PHA-893,888, whose efficacy may be influenced by PTPN6 expression. Knocking down PTPN6 expression inhibited the proliferation and migration of colorectal cancer cells in vitro, confirming its oncogenic role in this cancer type. This pan-cancer analysis establishes PTPN6's multifaceted influence on tumor immunity and its potential as a biomarker and therapeutic target."

Journal • Brain Cancer • CNS Tumor • Colorectal Cancer • Glioblastoma • Melanoma • Oncology • Sarcoma • Solid Tumor • PTPN6

Rationally modified SNX-class Hsp90 inhibitors disrupt extracellular fibronectin assembly without intracellular Hsp90 activity. (PubMed, RSC Med Chem) - "Through the rational modification of known Hsp90 inhibitors (SNX2112 and SNX25a) we developed four Hsp90 inhibitory compounds, whose alterations restricted their interaction with intracellular Hsp90 and did not stimulate the HSR. Two of the modified cohort (compounds 10 and 11) were able to disrupt the assembly of the extracellular fibronectin network at non-cytotoxic concentrations, and thus represent promising new tool compounds for studying the druggability of eHsp90 as a target for inhibition of tumour invasiveness and metastasis."

Journal • Oncology • CDC37

DRN-CDR: A cancer drug response prediction model using multi-omics and drug features. (PubMed, Comput Biol Chem) - "The drugs such as Tivozanib, SNX-2112, CGP-60474, PHA-665752, Foretinib etc., exhibited low median IC50 values and were found to be effective anti-cancer drugs. The case studies with different TCGA cancer types also revealed the effectiveness of SNX-2112, CGP-60474, Foretinib, Cisplatin, Vinblastine etc. This consistent pattern strongly suggests the effectiveness of the model in predicting CDR."

Journal • Oncology

ZNF695, A Potential Prognostic Biomarker, Correlates with Immune Infiltrates in Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma: Bioinformatic Analysis and Experimental Verification. (PubMed, Curr Gene Ther) - "ZNF695 may be a potential prognostic biomarker and immunotherapeutic target for CESC patients."

Biomarker • IO biomarker • Journal • Cervical Cancer • Oncology • Squamous Cell Carcinoma

Identification of circRNA-miRNA-mRNA network regulated by Hsp90 in human melanoma A375 cells. (PubMed, Comb Chem High Throughput Screen) - "Targeting the ITG-COL network is a promising approach to the treatment of melanoma."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • HSP90AA1

Integrated profiling uncovers prognostic, immunological, and pharmacogenomic features of ferroptosis in triple-negative breast cancer. (PubMed, Front Immunol) - "The high-risk group had a higher response to anti-PD-1 blockade or sunitinib, and the low-risk group had higher sensitivity to cisplatin. Two Cancer Therapeutics Response Portal (CTRP)-derived agents (SNX-2112 and brefeldin A) and PRISM-derived agents (MEK162, PD-0325901, PD-318088, Ro-4987655, and SAR131675) were predicted, which were intended for high-risk patients. Altogether, our findings unveil prognostic, immunological, and pharmacogenomic features of ferroptosis in TNBC, highlighting the potential clinical utility of ferroptosis in TNBC therapy."

Biomarker • IO biomarker • Journal • Breast Cancer • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer

Novel Diagnostic and Therapeutic Options for KMT2A-Rearranged Acute Leukemias. (PubMed, Front Pharmacol) - "We observed that KMT2A-r cell lines were more sensitive to 5-Fluorouracil (5FU), Gemcitabine (both antimetabolite chemotherapy drugs), WHI-P97 (JAK-3 inhibitor), Foretinib (MET/VEGFR inhibitor), SNX-2112 (Hsp90 inhibitor), AZD6482 (PI3Kβ inhibitor), KU-60019 (ATM kinase inhibitor), and Pevonedistat (NEDD8-activating enzyme (NAE) inhibitor). Moreover, IC50 data from analyses of ex-vivo drug sensitivity to small-molecule inhibitors reveals that Foretinib is a promising drug option for AML patients carrying FLT3 activating mutations. Thus, we provide novel and accurate options for the diagnostic screening and therapy of KMT2A-r leukemia, regardless of leukemia subtype."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CSPG4 • FLT3 • JAK3 • KMT2A • PIK3CB

Inhibition of HSP 90 is associated with potent anti-tumor activity in Papillary Renal Cell Carcinoma. (PubMed, J Exp Clin Cancer Res) - "These results demonstrate that HSP90 inhibition is associated with potent activity in PRCC, and implicate the PI3K/AKT and MEK/ERK1/2 pathways as important mediators of tumorigenesis. These data also provide the impetus for further clinical evaluation of HSP90, AKT, MEK or E2F pathway inhibitors in PRCC."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • AKT1 • HSP90AA1 • MET • PRCC

A gene prognostic index from cellular senescence predicting metastasis and radioresistance for prostate cancer. (PubMed, J Transl Med) - "We found that CSGPI might serve as an effective biomarker predicting metastasis probability and radioresistance for PCa and proposed that immune evasion was involved in the process of PCa metastasis."

Journal • Genito-urinary Cancer • Immune Modulation • Inflammation • Oncology • Prostate Cancer • Solid Tumor • ALDH2 • PD-L2

Ferroptosis Activation Scoring Model Assists in Chemotherapeutic Agents' Selection and Mediates Cross-Talk With Immunocytes in Malignant Glioblastoma. (PubMed, Front Immunol) - "Critically, potential drugs target to high scoring samples are predicted, namely, SNX2112, AZ628, and bortezomib and five compounds from the CellMiner database. Taken together, ferroptosis associates with glioblastoma aggressiveness, cross-talk with immunocytes and offer novel chemotherapy strategy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

SNX-2112 Induces Apoptosis and Inhibits Proliferation, Invasion, and Migration of Non-Small Cell Lung Cancer by Downregulating Epithelial-Mesenchymal Transition via the Wnt/β-Catenin Signaling Pathway. (PubMed, J Cancer) - "In conclusion, the current study is the first to discover the mechanism of SNX-2112 in NSCLC. SNX-2112 induced apoptosis and also inhibited the proliferation, invasion, and migration of NSCLC cells by downregulating EMT via the Wnt/β-catenin signaling pathway."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CDH1 • VIM

Complex Crystal Structure Determination and in vitro Anti-non-small Cell Lung Cancer Activity of Hsp90 Inhibitor SNX-2112. (PubMed, Front Cell Dev Biol) - "Based on the complex crystal structure and molecular interaction analysis, 32 novel SNX-2112 derivatives were designed, and 25 new ones displayed increased binding force with the target Hsp90 verified by molecular docking evaluation. The results would provide new references and guides for anti-NSCLC new drug development based on the lead compound SNX-2112."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HSP90AA1

Suppression of Esophageal Cancer Stem-like Cells by SNX-2112 Is Enhanced by STAT3 Silencing. (PubMed, Front Pharmacol) - "Finally, STAT3 overexpression eliminated the apoptotic and antiproliferative effects of SNX-2112 on ECSLCs. Hence, these results provide a rationale for the therapeutic potential of the combination of SNX-2112 with shSTAT3 in esophageal cancer, and may indicate new targets for clinical intervention in human cancer."

Journal • Esophageal Cancer • Gastrointestinal Cancer • Movement Disorders • Oncology • ABCB1 • ABCG2 • MAPK8 • STAT3

Antitumorigenic Effect of Hsp90 Inhibitor SNX-2112 on Tongue Squamous Cell Carcinoma is Enhanced by Low-Intensity Ultrasound. (PubMed, Onco Targets Ther) - "The most probable mechanism was that US sonoporation induced more SNX-2112 delivery to the cells and enhanced ROS production, triggering the ERS-associated apoptosis signaling pathway. Therefore, low-intensity US may increase the efficiency of conventional chemotherapy and reduce the dosage of SNX-2112 required and its side effects."

IO Biomarker • Journal • Oncology • Squamous Cell Carcinoma • BCL2

Ultrafast Low-Temperature Photothermal Therapy Activates Autophagy and Recovers Immunity for Efficient Antitumor Treatment. (PubMed, ACS Appl Mater Interfaces) - "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...A unique mechanism that achieves remarkable therapeutic performance was discovered, where over-activated 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 anti-recurrence treatment."

Journal • Oncology • Pain

CFTR interacts with Hsp90 and regulates the phosphorylation of AKT and ERK1/2 in colorectal cancer cells. (PubMed, FEBS Open Bio) - "Inhibition of Hsp90 by SNX-2112 induced the degradation of phosphorylated AKT and ERK1/2 in Caco2 and HRT18 cells. These findings may help provide insights into the physiological role of CFTR in CF-related diseases."

IO Biomarker • Journal

Identification of the circRNA-miRNA-mRNA regulatory network of Hsp90 inhibitor-induced cell death in colorectal cancer by integrated analysis. (PubMed, Gene) - "In this study, Caco-2 cells were treated with 0.25 μM SNX-2112, an Hsp90 inhibitor, for 48 h; subsequently, whole-transcriptome sequencing was performed...The circRNA-miRNA-mRNA regulatory network of Hsp90 inhibitor-induced cell death in colorectal cancer was constructed. This regulatory network extends the underlying mechanism of Hsp90 and improves our understanding of Hsp90 inhibitors as potential targeted therapeutic agents."

Journal

Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway. (PubMed, Oxid Med Cell Longev) - "Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance."

IO Biomarker • Journal

Tsc1 expression as a predictive biomarker of bladder cancer response to Hsp90 inhibitors (AUA 2019) - "The ATP-competitive Hsp90 inhibitors ganetespib and SNX2112 were used to challenge bladder cancer cell lines. Tsc1 expression appears to serve as a predictive biomarker of bladder cancer response to Hsp90 inhibitors. Additionally absence of Tsc1 leads to hypo-acetylation of Hsp90 and reduce binding to its inhibitors. Thus, HDAC inhibitors alone or in combination with Hsp90 inhibitors should be explored as a potential therapeutic approach in TSC1-null bladder cancers."

Biomarker