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A recent review on developing therapeutic proteins by engineering ligand receptor interactions examines these methods. The recent structural studies about the ternary complex of N and C terminal domains of IGFBP 4 with IGF 1 are a significant step in this direction. But, two major problems will Bosutinib need to be tackled for establishing IGFBPs as IGF antagonist based therapeutics: the IGFBPs should be protease resistant so as to become more effective in inhibiting IGF 1R signaling and IGFindependent steps should be handled so that they do not stall the beneficial effects of IGF 1 binding, including integrin engagement by IGFBP 1 and IGFBP 2 through their RGD motifs. The primary aim is possible by developing protease resistant types of IGFBP. Numerous proteases control IGFBP levels extracellularly, Papillary thyroid cancer dissociating the IGFBP IGF complex thereby increasing IGF 1/2 readily available for interacting with the IGF 1R. That is based on the differential effects of IGFBP 3 in cyst versus. normal prostate cells, when IGF 1 bio-availability is improved via PSA mediated IGFBP proteolysis. Hence, there's a need for understanding the structural mechanisms involved in proteolysis as a way to develop protease resistant IGFBPs with enhanced IGF inhibitory activities. The second objective is harder as a number of IGF 1 independent activities have already been noted. But, an initial step in the case of IGFBP 2 will be to modify its RGD motif by mutagenesis to abrogate integrin binding capacity. Raising the IGF binding affinity of the IGFBPs Developing IGFBPs as IGF antagonists for cancer therapeutics also contributes to the issue of whether the Cilengitide IGFBP binding affinity for the IGFs can be further enhanced. One starting point for design enhanced antagonists is to introduce variations with the purpose of improving their IGF binding affinity. An alternate approach will be to create novel chimeric protein constructs containing the D and C terminal domains obtained from different IGFBPs. This exploits the variations in affinity of D and C terminal domains of different IGFBPs in binding IGFs. For instance, 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 might bind to IGF 1 more efficaciously than either individual protein. Chimeric proteins have now been utilized in the past in drug development to impart properties from all of the parent proteins for the drug. Anti-diabetic effects of IGFBP 2 Little is known in regards to the potential toxicities as therapeutic agents in cancer or other diseases linked to the use of IGFBPs. What is known comes from studies in mice where IGFBP2 overexpression can promote glioma development and progression. Although this could be true for other cancers, this effect is likely due to integrin engagement by the IGFBP 2 RGD motif.