8OLU

Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

Summary for 8OLU

• Entry DOI: 10.2210/pdb8olu/pdb
• EMDB information: 16963
• Descriptor: Proteasome subunit alpha type, Proteasome subunit beta, Proteasome beta 6 subunit, putative, ... (15 entities in total)
• Functional Keywords: proteasome 20s subunit, unknown function
• Biological source: Leishmania tarentolae; More
• Total number of polymer chains: 28
• Total formula weight: 848365.08

Authors

Rowland, P. (deposition date: 2023-03-30, release date: 2023-08-09, Last modification date: 2023-08-23)

Primary citation

Thomas, M.G.,McGonagle, K.,Rowland, P.,Robinson, D.A.,Dodd, P.G.,Camino-Diaz, I.,Campbell, L.,Cantizani, J.,Castaneda, P.,Conn, D.,Craggs, P.D.,Edwards, D.,Ferguson, L.,Fosberry, A.,Frame, L.,Goswami, P.,Hu, X.,Korczynska, J.,MacLean, L.,Martin, J.,Mutter, N.,Osuna-Cabello, M.,Paterson, C.,Pena, I.,Pinto, E.G.,Pont, C.,Riley, J.,Shishikura, Y.,Simeons, F.R.C.,Stojanovski, L.,Thomas, J.,Wrobel, K.,Young, R.J.,Zmuda, F.,Zuccotto, F.,Read, K.D.,Gilbert, I.H.,Marco, M.,Miles, T.J.,Manzano, P.,De Rycker, M.
Structure-Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors.
J.Med.Chem., 66:10413-10431, 2023

PubMed Abstract: 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 proteasome. A related analogue, active against , 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 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.

PubMed: 37506194
DOI: 10.1021/acs.jmedchem.3c00582

Experimental method

ELECTRON MICROSCOPY (2.59 Å)