Q1 · MEDICINE
Article
Author: Edwards, Darren ; Read, Kevin D ; Miles, Timothy J ; De Rycker, Manu ; Osuna-Cabello, Maria ; Riley, Jennifer ; MacLean, Lorna ; Manzano, Pilar ; Zmuda, Filip ; Simeons, Frederick R C ; Camino-Díaz, Isabel ; Mutter, Nicole ; Stojanovski, Laste ; Zuccotto, Fabio ; Ferguson, Liam ; Wrobel, Karolina ; Hu, Xiao ; Thomas, John ; Castañeda, Pablo ; Craggs, Peter D ; Paterson, Christy ; McGonagle, Kate ; Marco, Maria ; Young, Robert J ; Goswami, Panchali ; Rowland, Paul ; Pont, Caterina ; Gilbert, Ian H ; Frame, Laura ; Martin, Julio ; Cantizani, Juan ; Thomas, Michael G ; Fosberry, Andrew ; Dodd, Peter G ; Conn, Daniel ; Pinto, Erika G ; Campbell, Lorna ; Peña, Imanol ; Robinson, David A ; Shishikura, Yoko ; Korczynska, Justyna
There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.