Aldoxorubicin

Aldoxorubicin

Identifiers
IUPAC name N-[[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
CAS Number	1361644-26-9
PubChem CID	71300693
ChemSpider	7986464
UNII	C28MV4IM0B
KEGG	D10383
ECHA InfoCard	100.244.879
Chemical and physical data
Formula	C37H42N4O13
Molar mass	750.758 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](CC3=C(C4=C(C(=C23)O)C(=O)C5=C(C4=O)C=CC=C5OC)O)(C(=NNC(=O)CCCCCN6C(=O)C=CC6=O)CO)O)N)O
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)/t17-,20-,22-,27-,32+,37-/m0/s1 Key:OBMJQRLIQQTJLR-FRTGXRTISA-N

Aldoxorubicin (INNO-206) is a tumor-targeted doxorubicin conjugate in development by CytRx. Specifically, it is the (6-maleimidocaproyl) hydrazone of doxorubicin. Essentially, this chemical name describes doxorubicin attached to an acid-sensitive linker (N-ε-maleimidocaproic acid hydrazide, or EMCH).

The proposed mechanism of action is as follows:

1. After administration, aldoxorubicin rapidly binds endogenous circulating albumin through the EMCH linker.
2. Circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including heart, bone marrow and gastrointestinal tract.
3. Once albumin-bound aldoxorubicin reaches the tumor, the acidic environment of the tumor causes cleavage of the acid sensitive linker.
4. Free doxorubicin is released at the site of the tumor.

Clinical trials

Five phase I trials for safety characterization have been completed. Several phase II and III trials are underway.

Phase II

As of January 2017, there are 6 phase II clinical trials in progress:

1. Second-line therapy for patients with glioblastoma
2. Treatment of HIV-positive patients with Kaposi's sarcoma
3. Combination therapy of ifosfamide and aldoxorubicin for treatment of metastatic or locally advanced sarcoma
4. Comparison of aldoxorubicin to the gold-standard treatment, topotecan, for metastatic small cell lung cancer
5. Treatment of advanced or metastatic pancreatic ductal adenocarcinoma
6. Comparison of aldoxorubicin and doxorubicin for patients with metastatic or locally advanced carcinoma

Phase III

A phase III trial for patients with relapsed soft tissue sarcoma comparing aldoxorubicin with several other chemotherapeutics is expected to complete in 2018. In November 2016, CytRx announced that preliminary results had been positive.

Further reading

• Kratz F, Azab S, Zeisig R, Fichtner I, Warnecke A (January 2013). "Evaluation of combination therapy schedules of doxorubicin and an acid-sensitive albumin-binding prodrug of doxorubicin in the MIA PaCa-2 pancreatic xenograft model". International Journal of Pharmaceutics. 441 (1–2): 499–506. doi:10.1016/j.ijpharm.2012.11.003. PMID 23149257.
• Walker L, Perkins E, Kratz F, Raucher D (October 2012). "Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative". International Journal of Pharmaceutics. 436 (1–2): 825–32. doi:10.1016/j.ijpharm.2012.07.043. PMC 3465682. PMID 22850291.
• Kratz F, Warnecke A (December 2012). "Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems". Journal of Controlled Release. 164 (2): 221–35. doi:10.1016/j.jconrel.2012.05.045. PMID 22705248.
• Sanchez E, Li M, Wang C, Nichols CM, Li J, Chen H, Berenson JR (July 2012). "Anti-myeloma effects of the novel anthracycline derivative INNO-206". Clinical Cancer Research. 18 (14): 3856–67. doi:10.1158/1078-0432.CCR-11-3130. PMID 22619306. S2CID 7467600.