Mitomycin C

With our advanced “DrugLnk” synthesis platform and extensive experience in complex payload compound chemistry for antibody-drug conjugates (ADCs) development, Creative Biolabs provides highly customized ADC production services using mitomycin C as payload.

Mitomycin C (MC), an antibiotic that also possesses anti-tumor activities, was originally isolated from the microorganism Stveptomyces caespitosus. Since then, a number of structurally similar variants of MC have been discovered. Together with mitomycin C, this series of molecules are named mitomycins. Mitomycin C exhibits a variety of specific biological effects in mammalian cells, including selective suppression of DNA synthesis, stimulation of genetic recombination, mutagenesis, chromosome damage, and sister chromatid exchange. A variety of the enzymes have been demonstrated to activate MC, including NAD(P)H dehydrogenase and xanthine dehydrogenase, making it an appealing agent for intracellular tumor killing. Mitomycin C has been shown to exert a broad spectrum and potent cytotoxicity against several human neoplastic diseases and it is generally utilized as a chemotherapeutic agent in the treatment of various types of cancer, including colon, breast, and bladder cancer.

The molecular structure of Mitomycin C.

Mitomycin C Mode of Action (MOA)

In its innate structure, mitomycin C is inert towards nucleophiles but it changes into a highly reactive bis-electrophile once reduced. MC activation begins by the reduction of the MC quinone ring into a hydroquinone. This is a process that voluntarily eliminates methanol and result in a leucoaziridinomitosene structure, which is a bis-electrophile that enables the alkylation of cellular nucleophiles, including phosphate, bicarbonate, glutathione, and DNA. DNA alkylation is major MOA of mitomycin C induced cell killing. Continuous DNA alkylation at the 1 and 10 positions of the leucoaziridinomitosene produces a cytotoxic inter-strand crosslinker, which links the N2 of opposite deoxyguanosine residues at CpG sites on double stranded DNAs. Besides DNA alkylation, redox cycling and inhibition of rRNA also play important roles in the cytotoxic effects of mitomycin C. Moreover, one study has indicated that thioredoxin reductase (TrxR) is also a cellular target for MC and it is suggested that the inhibition of TrxR activity may also contribute to the mitomycin C toxicity.

Mitomycin C contains planar rings that are activated by photon-mediated cycloaddition to attack bases on opposite strands of the dsDNA (A, Nat Rev Cancer, 2011) and a representation of the synergetic mechanism between mitomycin C and MLN4924 to induce cell death. (B, Mol Cancer Ther, 2014).

Mitomycin C-based ADCs

Several previous studies are done to exploit methods to expand the therapeutic window of mitomycin C. For example, conjugates of MC with N-succinyl-chitosan (N-succinyl-chitosan-MC) and glycol-chitosan (glycol-chitosan-MC) showed improved in vitro drug release properties and enhanced anti-tumor activity. In addition, a MC-dextran (MMCD) conjugate has been synthesized and conjugated to an anti-integrin αvβ3 mAbs to form MMCD-mAb. This conjugate showed an increased effectiveness and safety profile in the treatment of choroidal neovascularization (CNV). As a leader in antibody production and bio-conjugation, Creative Biolabs offers novel linkers and conjugation strategies for the development of innovated mitomycin C-based ADCs.

Structure of MMCD-mAb (Invest. Ophthalmol. Vis. Sci., 2011).

With our well-established “DrugLnk” organic synthesis platform, the experienced scientists here at Creative Biolabs is dedicated to help you develop mitomycin C -linker complexes using readily available or customized linkers for antibody conjugation in a timely and cost-effective manner. Our customarily tailored services and high quality products will contribute greatly to the success of your projects.

Creative Biolabs also provides other various services regarding ADC development. Please feel free to contact us for more information and a detailed quote.

References：

1. Deans, A.J.; et al. DNA interstrand crosslink repair and cancer. Nat Rev Cancer. 2011, 11(7): 467-480.
2. Garcia, K.; et al. Nedd8-activating enzyme inhibitor MLN4924 provides synergy with mitomycin C through interactions with ATR, BRCA1/BRCA2, and chromatin dynamics pathways. Mol Cancer Ther. 2014, 13(6): 1625-1635.
3. Kamizuru, H.; et al. Monoclonal antibody-mediated drug targeting to choroidal neovascularization in the rat. Invest. Ophthalmol. Vis. Sci. 2001, 42(11): 2664-2672.