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A recent review on developing therapeutic proteins by design ligand receptor interactions examines these methods. The recent structural studies around the ternary complex of C and N terminal domains of Celecoxib IGFBP 4 with IGF 1 are a substantial part of this direction. But, two major difficulties must be tackled for building IGFBPs as IGF antagonist based therapeutics: the IGFBPs should be protease resistant so as to be far better in curbing IGF 1R signaling and IGFindependent actions should be handled so they don't stall the beneficial effects of IGF 1 binding, including integrin engagement by IGFBP 1 and IGFBP 2 through their RGD motifs. The first objective can be achieved by developing protease resistant forms of IGFBP. Quite a few proteases control IGFBP levels extracellularly, dissociating the Eumycetoma IGFBP IGF complex thereby growing IGF 1/2 available for interacting with the IGF 1R. That is on the basis of the differential effects of IGFBP 3 in tumor vs. normal prostate cells, when IGF 1 bioavailability is improved via PSA mediated IGFBP proteolysis. Hence, there is a requirement for understanding the structural mechanisms involved in proteolysis in order to produce protease resilient IGFBPs with increased IGF inhibitory actions. The second objective is more challenging as numerous IGF 1 separate actions have been described. Nevertheless, an initial part of the case of IGFBP 2 will be to modify its RGD motif by mutagenesis to abrogate integrin binding capacity. Growing the IGF binding affinity of the IGFBPs Developing IGFBPs as IGF antagonists for cancer therapeutics also contributes to the issue of whether the IGFBP binding affinity for the IGFs can be further improved. One starting point for engineering increased antagonists is always to introduce variations with the goal BAY 11-7082 of improving their IGF binding affinity. An alternative method will be to produce novel chimeric protein constructs containing the D and C terminal domains extracted from different IGFBPs. This uses the variations in affinity of C and D terminal domains of various IGFBPs in binding IGFs. For example, the C terminal domain of IGFBP 2 can be combined with the N terminal domain of IGFBP 3 or vice-versa. A chimeric protein produced in this way may bind to IGF 1 more efficaciously than either individual protein. Chimeric proteins have been used in the past in drug development to impart properties from each of the parent proteins to the resulting drug. Anti-diabetic effects of IGFBP 2 Little is known regarding the potential toxicities linked to the utilization of IGFBPs as therapeutic agents in cancer or other diseases. What's known comes from studies in mice where IGFBP2 overexpression can promote glioma development and progression. This result is probably because of integrin engagement by the IGFBP 2 RGD motif, although this may be correct for other cancers.