Development of Anti-Trx-1 Agents for the Treatment of Cancer using Chemical Protein Synthesis

Thioredoxin system comprises of thioredoxin reductase (TrxR), thioredoxin (Trx) and NADPH. This system plays a major role in many cellular functions, including maintain cellular redox homeostasis, control of transcriptional factors, synthesis of DNA, stimulate cell growth and inhibit apoptosis [1]. Clinically, Thioredoxin-1 (Trx-1) has been over expressed in many of solid tumors [2]. In this research we will focus on using chemical protein synthesis to be an effective tool to treat cancer and our main target will be Trx-1. Trx-1 is a small protein consists of 105 amino acids and a member of the dithiol-disulfide oxidoreductase protein family [3].

The role of thioredoxin system in the aggressive tumor growth makes it an attractive target to treat cancer. Many of currently available anti-tumor agents are affected thioredoxin system and especially TrxR, a number of agents aimed to modulate thioredoxin system by inhibiting Txr-1 and no such molecules have reach the clinic yet. The goal of this research is to develop inhibitors for Trx-1, which can be used as new drug candidates against cancer with fewer side effects. The total chemical synthesis of Trx-1 and the corresponding inhibitor will be based on Fmoc-SPPS and NCL.

References

1. Arnér, E.S. and A. Holmgren, Physiological functions of thioredoxin and thioredoxin reductase. European Journal of Biochemistry, 2000. 267(20): p. 6102-6109.
2. Powis, G. and W.R. Montfort, Properties and biological activities of thioredoxins. Annual Review of Pharmacology and Toxicology, 2001. 41(1): p. 261-295.

3. Holmgren, A., Thioredoxin. Annual review of biochemistry, 1985. 54(1): p. 237-271.