SNX-5422 / Esanex - LARVOL DELTA

Recent progress and structural insights of potential Hsp90 inhibitors as anticancer agents. (PubMed, Mol Divers) - "There are several heterocyclic small molecules under investigation in clinical studies, such as AUY922, SNX-5422, STA-9090, and others. This review also contained a patent of HSP90 inhibitors, which showed greater effectiveness. Therefore, the main objective of this paper is to summarize all recent developments in the creation of anticancer medications that target HSP90 inhibitors in order to treat anticancer disease."

Journal • Review • Oncology • CDC37

Drug Development. (PubMed, Alzheimers Dement) - "This investigation supports irisin signaling to promote memory function and indicates a mediating role of Hsp90a in the brain. Further analysis of hippocampal mRNA is needed to understand the influence of Hsp90a inhibition on irisin-mediated transcriptional changes."

Journal • CDC37

Influence of in vivo Hsp90α inhibition on irisin signaling to the brain (AAIC 2024) - "Directly following NOR day 2, animals received single administrations of irisin (100 mg/kg, i.p.) or vehicle control and selective Hsp90a inhibitor SNX-5422 (10 mg/kg, o.g.) or vehicle control...Conclusions : This investigation supports irisin signaling to promote memory function and indicates a mediating role of Hsp90a in the brain. Further analysis of hippocampal mRNA is needed to understand the influence of Hsp90a inhibition on irisin-mediated transcriptional changes."

Preclinical • Alzheimer's Disease • CDC37 • HSP90AA1

High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia. (PubMed, Biochem Pharmacol) - "We identified 9 compounds active against BCP-ALL (ABT-199/venetoclax, AUY922/luminespib, dexamethasone, EC144, JQ1, NVP-HSP990, paclitaxel, PF-04929113 and vincristine), but sparing normal cells. Ex vivo validations confirmed that the BCL2 inhibitor venetoclax exerts an anti-leukemic effect against all three ALL subgroups at nanomolar concentrations. Overall, this study points out the benefit of HTP screening application for drug repurposing to allow the identification of effective and clinically translatable therapeutic agents for difficult-to-treat childhood BCP-ALL subgroups."

Journal • Acute Lymphocytic Leukemia • Developmental Disorders • Genetic Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • KMT2A • PAX5

HSP90, a common therapeutic target for suppressing skin injury caused by exposure to chemically diverse classes of blistering agents. (PubMed, J Pharmacol Exp Ther) - "Topical treatment with known HSP90 inhibitors, SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuated these chemical-induced skin damage (reduction in overall skin injury and clinical scores). Due to difficulties in determining the exact nature of onsite chemical exposure, a potent drug that can suppress widespread cutaneous damage may find a great utility. Thus, we identified HSP90 as a common molecular regulator of cutaneous inflammation and injury by two distinct warfare vesicants: arsenicals and mustards; and HSP90 inhibitors afford significant protection against skin damage."

Journal • Inflammation • Pain • CXCL1 • HSP90AA1 • NLRP3

APPLICATIONS OF HIGH-THROUGHPUT DRUG SCREENING AS DRUG REPURPOSING STRATEGY FOR POOR OUTCOME SUBGROUPS OF PEDIATRIC B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2023) - "These consist of the Bcl-2 inhibitor ABT-199 (Venetoclax), the HSP90 inhibitors AUY922 (Luminespib), EC144, PF-04929113, NVP-HSP990, the BET bromodomain inhibitor JQ1, the microtubule polymer stabilizer Paclitaxel, as well as two agents of the classical chemotherapy for BCP-ALL, the glucocorticoid Dexamethasone and the antimitotic Vincristine...In the combination setting, we managed to couple Givinostat, our previously established compound active for CRLF2r ALL cases, with Trametinib (ZIP synergy 7.04 and 16.83 for MUTZ-5 and MHH-CALL-4 respectively) or Venetoclax (ZIP synergy 9.23 and 5.03), thus providing a successful synergistic targeting further confirmed in CRLF2r ALL blasts, whose synergistic mechanism of action is currently investigated. This study has highlighted the emerging benefit of HTP drug screening applications guiding the early design oftherapies for multiple or specific patient subgroups in an approach of repurposing drugs available in the..."

Clinical • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Developmental Disorders • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • CRLF2 • KMT2A

A phase 1B study of SNX-5422 plus carboplatin (C) and paclitaxel (P) in patients with advanced non-small-cell lung cancer (NSCLC). (ASCO 2017) - P1; "SNX-5422 added to C/P was well-tolerated at doses up to 100 mg/m2, and preliminary efficacy of this combination in NSCLC warrants further study."

Clinical • P1 data • Biosimilar • Gene Therapies • Non Small Cell Lung Cancer • Pain

Preclinical efficacy of the HSP90 inhibitor SNX-5422 in targeting C481S mutant BTK and ibrutinib resistant CLL (AACR 2018) - P1; "We therefore propose that upon molecular relapse, the use of SNX-5422 may prevent clinical relapse and deepen the response to ibrutinib. A phase 1 study is currently open at Ohio State to investigate whether the addition of SNX-5422 to an established dose of ibrutinib can eliminate the C481S mutant clone and prevent or delay disease progression in subjects with CLL .EH and JAW contributed equally as senior authors."

Preclinical • Chronic Lymphocytic Leukemia • Indolent Lymphoma

Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers. (PubMed, Lung Cancer) - "The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs."

Clinical • Journal • P1 data • Lung Cancer • Neuroendocrine Tumor • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • EGFR • HER-2 • KRAS • RET

Oral Hsp90 inhibitor SNX-5422 attenuates SARS-CoV-2 replication and dampens inflammation in airway cells. (PubMed, iScience) - "Additionally, SNX-5422 interrupted expression of host factors demonstrated to be crucial for SARS-CoV-2 replication. Development of SNX-5422 as SARS-CoV-2-early-therapy will dampen disease severity, resulting in better clinical outcomes and reduced hospitalizations."

Journal • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Molecular Characterization and Elucidation of Pathways to Identify Novel Therapeutic Targets in Pulmonary Arterial Hypertension. (PubMed, Front Physiol) - "Protein-drug interactions indicated that two compounds, namely, nedocromil and SNX-5422, affect the identification of PAH candidate biomolecules... In conclusion, several lung tissue-derived molecular signatures, highlighted in this study, might serve as novel evidence for elucidating the essential mechanisms of PAH. The potential drugs associated with these molecules could thus contribute to the development of diagnostic and therapeutic strategies to ameliorate PAH."

Journal • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • FOXC1 • GATA2 • HSP90AA1 • HSPH1 • MIR106B • MIR17 • MIR20A • SPP1

Plasmodium falciparum SURFIN forms an intermediate complex with PTEX components and Pf113 during export to the red blood cell. (PubMed, Parasitol Int) - "Using an inducible translocon-clogged mini-SURFIN, we found that a stable translocation intermediate complex forms at the parasite plasma membrane and contains EXP2 and a processed form of Pf113. These results suggest a potential role of Pf113 for the translocation step of mini-SURFIN, providing further insights into the translocation mechanisms for parasite integral membrane proteins."

Journal • Infectious Disease • Malaria

Preclinical evaluation of the Hsp90 inhibitor SNX-5422 in ibrutinib resistant CLL. (PubMed, J Hematol Oncol) - "Furthermore the combination of SNX-5422 and ibrutinib provided a remarkable in vivo survival benefit in the Eμ-TCL1 mouse model of CLL compared to the vehicle or single agent groups (51 day median survival in the vehicle and ibrutinib groups versus 100 day median survival in the combination). We report here preclinical data suggesting that the Hsp90 inhibitor SNX-5422, which has been pursued in clinical trials in both solid tumor and hematological malignancies, is a potential therapy for ibrutinib resistant CLL."

Journal • Preclinical • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

Transcriptomics analysis of SNX-2112 on immune and mitochodrial genes (AACR 2018) - "...SNX-5422 is the orally active prodrug of SNX-2112, a highly selective inhibitor of heat-shock protein 90 (Hsp90) that has shown anti-tumor activity in clinical trials... SNX-2112 increased multiple suppressed immune-related genes and downregulated multiple overexpressed immune-related genes in A375 and K562 cell lines. Anti-tumor activity of SNX-2112 appears to be, in part, the result of interference with onco-metabolic pathways. Inhibition of IDO1 and TDO2 suggests possibly enhanced anti-tumor activity in combination with checkpoint inhibitors."

IO Biomarker • Leukemia • Melanoma

[VIRTUAL] Enhanced Sensitivity of Human Glioma Cells for Temozolomide (TMZ) by Combining Therapy With Heat Shock Protein 90 (SNO 2020) - "We also examined the ability of SNX-5422 to cross the blood brain barrier (BBB) and to achieve target inhibition in vivo. SNX-5422 is effective in downregulating Hsp90 client proteins required for glioma cell survival. In addition, SNX-5422 inhibits tumor growth by promoting apoptosis through modulation of several key signaling pathways and sensitizes glioma cells to TMZ. Given also that SNX-5422 crosses BBB, it warrants further investigation as a clinical agent for treatment of gliomas."

Glioma • Oncology • Solid Tumor

Heat Shock Protein 90 Inhibitors AUY922, BIIB021 and SNX5422 Induce Bim-mediated Death of Thyroid Carcinoma Cells. (PubMed, Anticancer Res) - "AUY922, BIIB021 and SNX5422 induce cytotoxicity by modulating Bim and ERK1/2, AKT and AMPK signaling in thyroid carcinoma cells."

Journal • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma

Deciphering the Inhibition Mechanism of under trial Hsp90 Inhibitors and their Analogues: A Comparative Molecular Dynamics Simulation. (PubMed, J Chem Inf Model) - "Results yielded new insights into the design of cancer therapeutic drugs against Hsp90. This finding suggests that under trial Hsp90 inhibitors MPC-3100 could be a potential starting point into the development of potential anti-cancer agents with the possibility of future directions for the improvement of early existing Hsp90 inhibitors CNF-2024 and SNX-5422 as an anti-cancer agent."

Journal • Breast Cancer • Colorectal Cancer • Lung Cancer • Oncology • Solid Tumor

Mild microwave ablation combined with HSP90 and TGF‑β1 inhibitors enhances the therapeutic effect on osteosarcoma. (PubMed, Mol Med Rep) - "In addition, the results indicated that the expression of cytochrome c, caspase‑3 and caspase‑9 were upregulated in response to the treatment, which indicated that the mitochondrial apoptotic signalling pathway had been activated. These findings may provide a novel strategy for the development of microwave ablation in osteosarcoma treatment, which could effectively kill tumour cells without damaging the surrounding normal tissues."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

A phase IB dose-escalation study of the HSP90 inhibitor SNX-5422 and erlotinib in patients with EGFR-mutant lung cancer and acquired resistance to EGFR tyrosine kinase inhibitors (ESMO 2014) - Presentation time: 27.09.2014, 12:45 - 13:45; Abstract #1288P; P1b, N=17; “SNX-5422 and E is a well-tolerated combination at dose levels up to SNX-5422 50 mg/m2 qod + E 150 mg. The MTD was declared SNX-5422 50 mg/m2 + E.”

P1 data • Non Small Cell Lung Cancer • Oncology

Esanex announces first patient dosed in an open-label study of SNX-5422 in chronic lymphocytic leukemia (Businesswire) - "Esanex...announced the first patient has been dosed in an open-label study of SNX-5422 added to ibrutinib in chronic lymphocytic leukemia (CLL) subjects with residual disease (clinicaltrials.gov ID#NCT02973399)."

Enrollment open • Hematological Malignancies • Oncology

Hsp90 inhibitor SNX-2112 enhances neoantigen presentation on the surface of tumor cells (AACR 2019) - "Introduction: SNX-5422 is the orally active prodrug of SNX-2112, a potent, highly selective inhibitor of heat-shock protein 90 (Hsp90) with promising anti-tumor activity in clinical trials. SNX-2112 increased surface expression of multiple MHC class I complexes. Results suggest that SNX-2112 can drive the selective surface presentation of Hsp90 client proteins on tumor cell surface and could improve recognition by T cells specific for various cancer-associated antigens derived from mutated genes, making it potential useful in immunotherapy of cancer. This effect of SNX-2112 is independent of the induction of apoptosis as agents like vemurafenib did not elicit the same effect."

IO Biomarker • Late-breaking abstract • PD(L)-1 Biomarker • Tumor-specific neoantigens

Efficacy and Safety of SNX-5422 Added to an Established Dose of Ibrutinib in CLL (clinicaltrials.gov) - P1; N=5; Terminated; Sponsor: Esanex Inc.; Active, not recruiting ➔ Terminated; Low recruitment

Clinical • Trial termination