Drugs for 'protein clouds': targeting intrinsically disordered transcription factors.
Transcription factors (TFs) are very attractive but difficult drug targets. The difficulties come from several directions including the binding promiscuity of TFs and the intrinsically disordered nature of their binding sites, which often resemble 'protein clouds'. For a long time the targeting of proteins without defined structures was considered infeasible. Data have now emerged showing that selective blocking of specific interactions of intrinsically disordered TFs with their protein binding partners is possible. Initial hits have been optimized to increase their specificity and affinity. Several strategies have been elaborated for elucidating the mechanisms of blocking of intrinsic disorder-based protein-protein interactions. However, challenges remain in the field of drug development for 'protein clouds'; such development is still in its earliest stage.
Dunker
A Keith
AK
Institute for Intrinsically Disordered Protein Research, The Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. kedunker@iupui.edu
Uversky
Vladimir N
VN
D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D034802:RNA-Binding Protein EWS; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
D004268:DNA-Binding Proteins; C106031:EWS-FLI fusion protein; C116115:MYCBP protein, human; D015514:Oncogene Proteins, Fusion; D004364:Pharmaceutical Preparations; D011506:Proteins; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors