DOXO-EMCH

• CAT Number: I001876
• CAS Number: 151038-96-9
• Molecular Formula: C37H42N4O13
• Molecular Weight: 750.75
• Purity: ≥95%
• Synonyms: INNO-206; DOXO-EMCH; N-[(Z)-[1-[(2S,4S)-4-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]-2-hydroxyethylidene]amino]-6-(2,5-dioxopyrrol-1-yl)hexanamide
• Target: Topoisomerase
• Solubility: 10 mM in DMSO
• Storage: Store at -20°C
• IC50: N/A
• IUPAC Name: N-[(E)-[1-[(2S,4S)-4-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]-2-hydroxyethylidene]amino]-6-(2,5-dioxopyrrol-1-yl)hexanamide
• InChI: InChI=1S/C37H42N4O13/c1-17-32(46)20(38)13-27(53-17)54-22-15-37(51,23(16-42)39-40-24(43)9-4-3-5-12-41-25(44)10-11-26(41)45)14-19-29(22)36(50)31-30(34(19)48)33(47)18-7-6-8-21(52-2)28(18)35(31)49/h6-8,10-11,17,20,22,27,32,42,46,48,50-51H,3-5,9,12-16,38H2,1-2H3,(H,40,43)/b39-23+/t17-,20-,22-,27-,32+,37-/m0/s1
• InChIKey: OBMJQRLIQQTJLR-USGQOSEYSA-N
• SMILES: C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](CC3=C2C(=C4C(=C3O)C(=O)C5=C(C4=O)C(=CC=C5)OC)O)(/C(=N/NC(=O)CCCCCN6C(=O)C=CC6=O)/CO)O)N)O

Doxo-EMCH (Cat No.:I001876), also known as Doxorubicin-EMCH or PL-DOXO, is a prodrug of the widely used anticancer drug doxorubicin. Doxo-EMCH is designed to improve the delivery and targeting of doxorubicin to tumor cells. It is composed of a modified form of doxorubicin conjugated to a hydrophilic polymer, which helps to enhance its solubility and stability. Upon administration, Doxo-EMCH undergoes enzymatic cleavage, releasing doxorubicin within the tumor microenvironment. This prodrug approach allows for targeted drug delivery, potentially reducing systemic toxicity and improving the therapeutic efficacy of doxorubicin in cancer treatment.

Reference

1. Clin Cancer Res. 2012 Jul 15;18(14):3856-67. doi: 10.1158/1078-0432.CCR-11-3130. Epub 2012 May 22.

Anti-myeloma effects of the novel anthracycline derivative INNO-206.

PURPOSE: Doxorubicin has shown efficacy especially in combination treatment for the treatment of multiple myeloma; however, its side effects limit its use. INNO-206 is an albumin-binding prodrug of doxorubicin, which is released from albumin under acidic conditions. Because INNO-206 has not been previously evaluated in any hematologic malignancy, we determined its anti-multiple myeloma effects. EXPERIMENTAL DESIGN: The anti-multiple myeloma effect of INNO-206 at different pH levels on multiple myeloma cell proliferation using multiple myeloma cell lines with the MTS assay and antiangiogenic activity using the chorioallantoic membrane/feather bud assay were determined. The anti-multiple myeloma effects and toxicity of INNO-206 were also compared with conventional doxorubicin and PEGylated liposomal doxorubicin (PLD) alone, and in combination with bortezomib, using our multiple myeloma xenograft models. RESULTS: INNO-206 inhibited blood vessel formation and reduced multiple myeloma cell growth in a pH-dependent fashion. INNO-206 alone produced marked anti-multiple myeloma effects in vivo at doses that doxorubicin was toxic, and the combination of INNO-206 plus bortezomib produced increased anti-multiple myeloma effects compared with either agent alone. In contrast, all mice receiving bortezomib with doxorubicin or PLD died. CONCLUSIONS: These findings show that INNO-206 produces anti-multiple myeloma effects in vitro and in vivo. It also enhances the antitumor effects of bortezomib. These results suggest that INNO-206 may provide patients with multiple myeloma with an anthracycline that may be administered safely at higher doses compared with free doxorubicin, resulting in superior efficacy compared with the currently available anthracyclines to treat this B-cell malignancy.

2. Invest New Drugs. 2010 Feb;28(1):14-9. doi: 10.1007/s10637-008-9208-2. Epub 2009 Jan 8.

INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model.

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (INNO-206) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that is being assessed clinically. The prodrug binds rapidly to circulating serum albumin and releases doxorubicin selectively at the tumor site. This novel mechanism may provide enhanced antitumor activity of doxorubicin while improving the overall toxicity profile. Preclinically, INNO-206 has shown superior activity over doxorubicin in a murine renal cell carcinoma model and in breast carcinoma xenograft models. In this work, we compared the antitumor activity of INNO-206 and doxorubicin at their respective maximum tolerated doses in three additional xenograft models (breast carcinoma 3366, ovarian carcinoma A2780, and small cell lung cancer H209) as well as in an orthotopic pancreas carcinoma model (AsPC-1). INNO-206 showed more potent antitumor efficacy than free doxorubicin in all tumor models and is thus a promising clinical candidate for treating a broad range of solid tumors.

3. Expert Opin Investig Drugs. 2007 Jun;16(6):855-66.

DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials.

The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats and dogs, including significantly reduced cardiotoxicity. After intravenous administration, DOXO-EMCH binds rapidly to the Cys-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. In a clinical Phase I study, the dose of doxorubicin could be increased by a factor of 4.5-340 mg/m(2) when 75 mg/m(2) of free doxorubicin is considered to be the dose that can be administered as a single agent concomitant with the typical spectrum of side effects (i.e., myelotoxicity and mucositis). DOXO-EMCH was able to induce tumor regressions in anthracycline-sensitive tumors (i.e., breast cancer, small cell lung cancer and sarcoma). Phase II studies will be initiated at the beginning of 2007.