CHR-3996 - CAS 1235859-13-8
Catalog number:
1235859-13-8
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
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Description:
CHR-3996 is an orally bioavailable, second-generation hydroxamic acid-based inhibitor of histone deacetylase (HDAC) with potential antineoplastic activity. HDAC inhibitor CHR-3996 inhibits HDAC, resulting in an accumulation of highly acetylated histones, the induction of chromatin remodeling, and the selective transcription of tumor suppressor genes; these events may result in the inhibition of tumor cell division and the induction of tumor cell apoptosis. This agent may upregulate HSP70 and downregulate anti-apoptotic Bcl-2 proteins more substantially than some first-generation HDAC inhibitors. HDACs, upregulated in many tumor cell types, are a family of metalloenzymes responsible for the deacetylation of chromatin histone proteins.
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Appearance:
Solid powder
Synonyms:
CHR-3996; CHR3996; CHR 3996.
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Current Developer:
Chroma Therapeutic
1.Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor.
Moffat D1, Patel S, Day F, Belfield A, Donald A, Rowlands M, Wibawa J, Brotherton D, Stimson L, Clark V, Owen J, Bawden L, Box G, Bone E, Mortenson P, Hardcastle A, van Meurs S, Eccles S, Raynaud F, Aherne W. J Med Chem. 2010 Dec 23;53(24):8663-78. doi: 10.1021/jm101177s. Epub 2010 Nov 16.
A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC₅₀ values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.
2.A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors.
Banerji U1, van Doorn L, Papadatos-Pastos D, Kristeleit R, Debnam P, Tall M, Stewart A, Raynaud F, Garrett MD, Toal M, Hooftman L, De Bono JS, Verweij J, Eskens FA. Clin Cancer Res. 2012 May 1;18(9):2687-94. doi: 10.1158/1078-0432.CCR-11-3165.
PURPOSE: This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.
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CAS 1235859-13-8 CHR-3996

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