SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in subjects who have residual disease, but have not progressed on ibrutinib after 18 months of monotherapy, and/or prevents or delays disease progression of subjects with CLL.

Start Date07 Feb 2017

Sponsor / Collaborator

Esanex, Inc.

NCT02914327 / WithdrawnPhase 1

A Phase 1, Open-label Study of SNX-5422 and Ibrutinib in Chronic Lymphocytic Leukemia Subjects With a Mutation in Bruton's Tyrosine Kinase

SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will result in the removal of mutated BTK from blood mononuclear cells and/or prevents or delays disease progression of subjects with CLL

Start Date02 Feb 2017

Sponsor / Collaborator

Esanex, Inc.

NCT02612285 / TerminatedPhase 2

A Single Arm Study of SNX-5422 in Subjects With TP53 Null Cancers

SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). Initial in vitro evidence supports that SNX-5422 may be active against TP53 null tumors irrespective of tumor type .

Start Date01 Mar 2016

Sponsor / Collaborator

Esanex, Inc.

100 Clinical Results associated with Esanex, Inc.

0 Patents (Medical) associated with Esanex, Inc.

Literatures (Medical) associated with Esanex, Inc.

01 Dec 2021·Journal of Hematology & Oncology

Preclinical evaluation of the Hsp90 inhibitor SNX-5422 in ibrutinib resistant CLL

Letter

Author: Orlemans, Eric ; Woyach, Jennifer A ; Chen, Timothy L ; Harrington, Bonnie ; Sloan, Shelby ; Truxall, Jean ; Alinari, Lapo ; Wasmuth, Ronni ; Lehman, Amy M ; Hertlein, Erin ; Prouty, Alexander ; Byrd, John C ; Baiocchi, Robert A ; Sampath, Deepa

AbstractB-cell receptor (BCR) antagonists such as the BTK inhibitor ibrutinib have proven to effectively target chronic lymphocytic leukemia (CLL) tumor cells, leading to impressive response rates in these patients. However patients do still relapse on ibrutinib, and the progressive disease is often quite aggressive requiring immediate treatment. Several strategies are being pursued to treat patients who relapse on ibrutinib therapy. As the most common form of relapse is the development of a mutant form of BTK which limits ibrutinib binding, agents which lead to degradation of the BTK protein are a promising strategy. Our study explores the efficacy of the Hsp90 inhibitor, SNX-5422, in CLL. The SNX Hsp90 inhibitor was effective in primary CLL cells, as well as B-cell lines expressing either BTK wild type or C481 mutant BTK, which has been identified as the primary resistance mechanism to ibrutinib in CLL patients. 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.

01 Dec 2021·Lung Cancer

Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers

Article

Author: Giuseppe Giaccone ; Alexander Drilon ; Zhonglin Hao ; Everardus Otto Orlemans ; Robin Guo ; Mark G. Kris ; Martin Gutierrez ; James M. Hinson ; Christie Hilton ; Stephen V. Liu

OBJECTIVESSingle-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers.MATERIALS AND METHODSIn part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m²) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m²) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m² SNX-5422 monotherapy qod for 21 days (28-day cycle).RESULTSTwenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m² qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion).CONCLUSIONSThe 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.

01 Jul 2019·Cancer Research

Abstract LB-187: Hsp90 inhibitor SNX-2112 enhances neoantigen presentation on the surface of tumor cells

Author: Walker, John W. ; Orlemans, Everardus ; Fahlman, Richard ; Lapointe, Paul ; Yap, Megan ; Baker, Kristi

AbstractIntroduction: 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-5422 enhanced anti-PD-1 activity in MC38 murine model. SNX-2112 affects multiple tumor pathways, including the interferon pathway and upregulates genes associated with antigen expression, and T-cell recognition, and it interferes with tumor microenvironment immunoediting associated genes.Methods: Cells were cultured in media supplemented with 10% fetal bovine serum at 37°C, 5% CO2, and 95% humidity. The 50% effective concentration of SNX-2112 on cell viability of SkMel28, MDAMB231, SkMel2 was determined using Cell Titer-Glo® Luminescent Cell Viability Assay. Cells were treated with SNX-2112 or other anti-tumor agents, e.g., vemurafenib, to determine surface expression of MHC class I complexes by flow cytometry using MHC class I monoclonal antibody PE conjugate (Enzo-Cat# ALX-805-711R-C100) and, in parallel, induction of apoptosis by Annexin V APC.Results: At the lowest dose of SNX-2112 required to inhibit activity of model Hsp90 clients (MAPK), a 3 to 5-fold increase in MHC class I presentation was observed in all cells lines. Treatment of MDAMB231 with SNX-2112 caused a 3-fold increase in surface expression of MHC class I complexes, loss of Hsp90 client protein activity, and increased protein ubiquitination, without change in protein levels of immunoproteasome subunits LMP2 and LMP7. Increased surface expression of MHC class I complexes, loss of Hsp90 client function, increased protein ubiquitination without affecting immunoproteasome subunits were also found in both melanoma cell lines. This suggests that upregulation of cell surface MHC class I complexes is driven by increased Hsp90 client protein turnover. SNX-2112 treatment at concentrations sufficient to increase MHC class I surface expression also resulted in a small increase in apoptosis. Interestingly, treatment of SkMel28 with vemurafenib robustly induced apoptosis without any effect on surface expression of MHC class I complexes. Analysis of surface-expressed peptides by mass spectrometry revealed a change in peptide profile after treatment with SNX-2112.Conclusion: 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. Ongoing studies are focused on identifying Hsp90 client-derived peptides in surface complexes and their role in anti-tumor immunity.Citation Format: Megan Yap, John W. Walker, Kristi Baker, Richard Fahlman, Everardus Orlemans, Paul Lapointe. Hsp90 inhibitor SNX-2112 enhances neoantigen presentation on the surface of tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-187.

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