Metal binding pharmacophore library yields discovery of inhibitors of the proteasome subunit Rpn11 and human Glyoxalase 1

Metalloproteins are essential in many biological processes and make up approximately one-third to one-half of the proteome. Metalloproteins utilize a metal ion cofactor that can serve a structural role, allow electron transfer, or catalyze an enzymatic reaction. Specifically, a metalloprotein that utilizes a metal ion in a catalytic role is referred to as a metalloenzyme. The catalytic activity of certain metalloenzymes has been associated with a number of diseases ranging from diabetes, cancer, depression, anxiety, and pathogenic infections.4 Therefore the development of novel therapeutics that target specific metalloenzymes in these diseased states is in great need. The use of fragment-based drug discovery (FBDD) through the use of metal-binding pharmacophores (MBP) libraries for metalloenzyme inhibitor development represents a unique opportunity. This dissertation will focus on utilizing FBDD for the discovery of novel metalloenzyme inhibitors. Two therapeutically relevant Zn2+-dependent enzymes, Rpn11 and GLO1, were chosen as targets. The use of a modest MBP fragment library to enable the discovery of a novel class of inhibitors for Rpn11 will be presented in Chapter 2. Chapter 3 details a synthetic campaign prompted by the discoveries discussed in Chapter 2, that lead to the development of a first-in-class potent Rpn11 inhibitor. The same FBDD approach was utilized for the development of a novel class of GLO1 inhibitors, which is described in Chapter 4. Lastly, a novel potent GLO1 inhibitor is described in Chapter 5