Q1 · MEDICINE
Article
Author: Thomas, Michael G ; Mutter, Nicole ; Zuccotto, Fabio ; Osuna-Cabello, Maria ; Paterson, Christy ; Wrobel, Karolina ; Conn, Daniel ; Campbell, Lorna ; Simeons, Frederick R C ; Ferguson, Liam ; Edwards, Darren ; Rowland, Paul ; Hu, Xiao ; McGonagle, Kate ; Shishikura, Yoko ; Zmuda, Filip ; Miles, Timothy J ; Goswami, Panchali ; Manzano, Pilar ; Stojanovski, Laste ; MacLean, Lorna ; Camino-Díaz, Isabel ; Read, Kevin D ; Castañeda, Pablo ; Cantizani, Juan ; Frame, Laura ; Thomas, John ; Martin, Julio ; Gilbert, Ian H ; Dodd, Peter G ; Robinson, David A ; Fosberry, Andrew ; Korczynska, Justyna ; Young, Robert J ; Riley, Jennifer ; Marco, Maria ; Pont, Caterina ; Craggs, Peter D ; Pinto, Erika G ; Peña, Imanol ; De Rycker, Manu
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.