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Ref Type Journal Article
PMID (25096516)
Authors Vesci L, Milazzo FM, Carollo V, Pace S, Giannini G
Title Preclinical antitumor activity of SST0116CL1: a novel heat shock protein 90 inhibitor.
Journal International journal of oncology
Vol 45
Issue 4
Date 2014 Oct
URL
Abstract Text 4-Amino substituted resorcino-isoxazole (SST0116CL1) (property of Sigma-Tau Research Switzerland S.A.) is a potent, second generation, small-molecule heat shock protein 90 inhibitor (Hsp90i). SST0116CL1 binds to the ATP binding pocket of Hsp90, and interferes with Hsp90 chaperone function thus resulting in client protein degradation and tumor growth inhibition. The aim of the study was to assess SST0116CL1 in various solid and haematological tumors. The antitumor properties of SST0116CL1 were assessed using in vitro cell proliferation and client protein degradation assays and in vivo different tumor xenograft models. Pharmacokinetic (PK) data were also generated in tumor-bearing mice to gain an understanding of optimal dosing schedules and regimens. SST0116CL1 was shown to inhibit recombinant Hsp90α and to induce the destabilization of different client proteins, often overexpressed and constitutively activated in different types of hematological or solid human tumors. In preclinical in vivo studies, it was revealed to induce antitumor effects in murine models of leukemia and of gastric and ovarian carcinoma. A modulation of PD biomarkers in terms of downregulation of Hsp90 client proteins in tumor-bearing mice was found. SST0116CL1 is a new clinical candidate for cancer therapy. The antitumor property of SST0116CL1, likely due to direct inhibition of the Hsp90 enzymatic activity, may prove to be a critical attribute as the compound enters phase I clinical trials.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SST0116CL1 SST0116CL1 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SST0116CL1 HSP90 Inhibitor 35 SST0116CL1 is a second-generation small molecule inhibitor of Hsp90, which leads to decreased expression of Hsp90 client proteins and reduced tumor cell proliferation and tumor growth (PMID: 25096516).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown stomach carcinoma not applicable SST0116CL1 Preclinical - Cell line xenograft Actionable In a preclinical study, SST0116CL1 inhibited tumor growth in cell line xenograft models of gastric carcinoma (PMID: 25096516). 25096516
Unknown unknown acute myeloid leukemia not applicable SST0116CL1 Preclinical - Cell line xenograft Actionable In a preclinical study, SST0116CL1 demonstrated antitumor activity in cell line xenograft models of acute myeloid leukemia (PMID: 25096516). 25096516
Unknown unknown Advanced Solid Tumor not applicable SST0116CL1 Preclinical - Cell culture Actionable In a preclinical study, SST0116CL1 inhibited proliferation of several human tumor cell lines in culture (PMID: 25096516). 25096516
Unknown unknown ovarian cancer not applicable SST0116CL1 Preclinical - Cell line xenograft Actionable In a preclinical study, SST0116CL1 inhibited tumor growth in p-glycoprotein over expressing ovarian cancer cell line xenograft models (PMID: 25096516). 25096516