MMAF-OMe - CAS 863971-12-4

MMAF-OMe - CAS 863971-12-4 Catalog number: BADC-00694

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MMAF-Ome is a methoxyl analogue of MMAF, used in antibody-drug conjugates (ADCs) as the antimitotic agent part. The methoxyl works as the reaction group. MMAF is a potent auristatin-derived antineoplastic agent, working by inhibition of tubulin polymerization. It exhibited cytotoxicity in Karpas 299, H3396, 786-O and Caki-1 cells with IC50 values of 119nM, 105nM, 257nM and 200nM after 96-hour treatment.

General Information

Category
ADCs Cytotoxin with Linkers
Product Name
MMAF-OMe
CAS
863971-12-4
Catalog Number
BADC-00694
Molecular Formula
C40H67N5O8
Molecular Weight
745.99

Chemical Structure

  • MMAF-OMe
Synonyms
MMAF-OMe, Monomethyl auristatin F methyl ester; methyl (2S)-2-[[(2R,3R)-3-methoxy-3-[(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-[methyl-[(2S)-3-methyl-2-[[(2S)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoate
Canonical SMILES
CCC(C)C(C(CC(=O)N1CCCC1C(C(C)C(=O)NC(CC2=CC=CC=C2)C(=O)OC)OC)OC)N(C)C(=O)C(C(C)C)NC(=O)C(C(C)C)NC
InChI Key
WRVLBJXFSHALRZ-FUVGGWJZSA-N
InChI
InChI=1S/C40H67N5O8/c1-13-26(6)35(44(9)39(49)34(25(4)5)43-38(48)33(41-8)24(2)3)31(51-10)23-32(46)45-21-17-20-30(45)36(52-11)27(7)37(47)42-29(40(50)53-12)22-28-18-15-14-16-19-28/h14-16,18-19,24-27,29-31,33-36,41H,13,17,20-23H2,1-12H3,(H,42,47)(H,43,48)/t26-,27+,29-,30-,31+,33-,34-,35-,36+/m0/s1
1.Targeted Drug Delivery with an Integrin-Binding Knottin-Fc-MMAF Conjugate Produced by Cell-Free Protein Synthesis
Currier NV, Ackerman SE, Kintzing JR, Chen R, Filsinger Interrante M, Steiner A, Sato AK, Cochran JR
Antibody-drug conjugates (ADC) have generated significant interest as targeted therapeutics for cancer treatment, demonstrating improved clinical efficacy and safety compared with systemic chemotherapy. To extend this concept to other tumor-targeting proteins, we conjugated the tubulin inhibitor monomethyl-auristatin-F (MMAF) to 2.5F-Fc, a fusion protein composed of a human Fc domain and a cystine knot (knottin) miniprotein engineered to bind with high affinity to tumor-associated integrin receptors. The broad expression of integrins (including αvβ3, αvβ5, and α5β1) on tumor cells and their vasculature makes 2.5F-Fc an attractive tumor-targeting protein for drug delivery. We show that 2.5F-Fc can be expressed by cell-free protein synthesis, during which a non-natural amino acid was introduced into the Fc domain and subsequently used for site-specific conjugation of MMAF through a noncleavable linker. The resulting knottin-Fc-drug conjugate (KFDC), termed 2.5F-Fc-MMAF, had approximately 2 drugs attached per KFDC. 2.5F-Fc-MMAF inhibited proliferation in human glioblastoma (U87MG), ovarian (A2780), and breast (MB-468) cancer cells to a greater extent than 2.5F-Fc or MMAF alone or added in combination. As a single agent, 2.5F-Fc-MMAF was effective at inducing regression and prolonged survival in U87MG tumor xenograft models when administered at 10 mg/kg two times per week. In comparison, tumors treated with 2.5F-Fc or MMAF were nonresponsive, and treatment with a nontargeted control, CTRL-Fc-MMAF, showed a modest but not significant therapeutic effect. These studies provide proof-of-concept for further development of KFDCs as alternatives to ADCs for tumor targeting and drug delivery applications. Mol Cancer Ther; 15(6); 1291-300.

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