Structural and functional analysis of cancer related proteins: A critical target for drug development

Abstract

Protein kinases are involved in cancer metabolism and have been targeted for structure‐based drug development. The crystals structures of several clinically important protein kinase‐inhibitor complexes have been determined, which provide the mechanism of inhibition of protein kinases. In our laboratory, we are working on structure and function analysis on two protein kinases e.g. (i) a non‐receptor tyrosine kinase expressed in hepatocellular carcinoma (TEC) and Class I Phosphoinositide 3‐Kinase (PI3K). We have cloned and expressed both kinases in E. coli and looking forward for biochemical and structural characterization of both proteins.In addition, we are also working on structural and biochemical characterization of Ergp55 protein belongs to Ets family of transcription factor. The Ergp55 is involved in various development processes and regulation of cancer metabolism. Using biochemical assay, we have identified the part of Ergp55 protein that mediates the auto‐inhibition using E74 and cfos promoter DNA sequences. We have also crystallized and solved the crystal structure of ETS domain of Ergp55 in native and its complexes with E74 and cFOS promoter DNA sequences. The structure analysis provides the insights into DNA sequence discrimination by ETS domain of Ergp55 protein. These studies will aid in designing the compounds, which stabilize the inhibited form of Ergp55 and inhibits its binding to DNA. Based on crystal structures, we have designed the DNA binding compounds, which interfere in ETS‐DNA binding and proved to be potential drugs against prostate cancer.