Prodrug-CB1954

Scientists at Creative Biolabs are expert in antibody/protein conjugation. Now we offer superior quality CB1954 as a prodrug for  antibody-nitroreductase conjugate-based antibody-directed enzyme prodrug therapy (ADEPT) development. Our high-quality products and services will promote your project development of innovative cancer treatments.

CB1954

CB1954 [5-(aziridin-l-yl)-2, 4-dinitrobenzamide] is a monofunctional alkylating agent. This agent represents one of the compounds showing a real anti-tumour selectivity. Previous studies suggested that CB1954 exhibited significantly and highly selective activity against the rat Walker 256 tumour. The principle is that CB1954 forms DNA interstrand crosslinks in Walker cells but not in insensitive cells. It is unexpected that the monofunctional alkylating agent has selectivity. And, it is obvious that the sensitivity of the Walker tumour towards CB1954 showed a unique biochemical feature. CB1954 has been described as a drug that human has searched for the treatment of tumor. In addition, the CB1954 can be a prodrug targeted to human tumours by conjugating to an antibody (ADEPT). Thus, CB1954 may have a potential role in the therapy of human tumours.

MOA of CB1954

As a prodrug, CB1954 [5-(aziridin-l-yl)-2,4-dinitrobenzamide] can be catalyzed by the nitroreductase enzyme and yield an effective drug 5-(azirdin-1-yl)-4-hydroxy-amino-2-nitro benzamide, which is a potent DNA interstrand crosslinking agent. The drug has displayed potency in the treatment of Walker carcinoma. Besides, this new compound can form interstrand crosslinks in the DNA of Chinese hamster V79 cells to which it is also highly toxic.

Mechanism of activation and of CB1954. Fig.1 Mechanism of activation and of CB1954. (Williams, 2015)

CB1954-based ADEPT

ADEPT is formed with a tumor-specific antibody (or antibody fragment) and a prodrug-specific enzyme. CB 1954 used as the potential prodrug of ADEPT is under active development. The antitumor prodrug CB 1954 can be activated to the cytotoxic metabolite 5-aziridin-1-yl-4-hydroxylamino-2-nitrobenzamide by E. coli nitroreductase. E. coli nitroreductase is efficient to activate CB 1954. Importantly, when a combination of E. coli nitroreductase with CB 1954, it was cytotoxic to V79 cells that were insensitive toward CB 1954 only. In addition, in other gene therapies, the infection of mammalian cells with a recombinant retrovirus containing the nitroreductase cDNA enhanced CB 1954 sensitivity with a bystander effect.

Principles of drug targeting using ADEP. Fig 2. Principles of drug targeting using ADEPT. (Thanki, 2015)

With our advanced technology platforms and experienced scientists for ADEPT, Creative Biolabs provides CB1954 as a prodrug for comprehensive antibody-nitroreductase conjugate-based ADEPT development. We also provide other products and services regarding ADEPT development. Please contact us for more information if you want to know about the service.

References

  1. Williams, E. M.; et al. Nitroreductase gene-directed enzyme prodrug therapy: insights and advances toward clinical utility. Biochemical Journal. 2015, 471(2), 131-53.
  2. Thanki, K.; et al. Recent Advances in Tumor Targeting Approaches. Targeted Drug Delivery: Concepts and Design. 2015, Springer International Publishing.

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