Development of biological response modifiers based on unique medicinal chemical strategy

Abstract

Chemical biology and structural development studies performed at The University of Tokyo during 19772020 are outlined chronologically. The studies are divided into three parts, i.e., (i) chemical biology of chemical carcinogenesis and molecular design of anti-tumor agents, (ii) structural development studies on biological response modifiers, and (iii) studies on so-called dramatype drug discovery focusing on pharmacological chaperones and protein knockdown-inducers. The first part describes analysis of DNA modification by Glu-P-1, which is a typical carcinogenic heterocyclic amine found in cooked foods, as well as molecular design of DNA-cleaving agents with anti-tumor properties. The second part deals with structural development studies of nuclear receptor ligands and various biological response modfiers derived from thalidomide, including the ligand superfamily concept and the multi-template strategy. The third part describes pharmacological chaperones that should be useful for the treatment of protein misfolding diseases, including Niemann-Pick type C disease and retinitis pigmentosa, and a protein knockdown strategy aimed at degradation of neurodegenerative-disease-causing polyglutamic aggregative proteins.