Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis

• Published in: Journal of medicinal chemistry 2021-05, Vol.64 (9), p.5905-5930
• Main Authors: Thomas, Michael, Brand, Stephen, De Rycker, Manu, Zuccotto, Fabio, Lukac, Iva, Dodd, Peter G, Ko, Eun-Jung, Manthri, Sujatha, McGonagle, Kate, Osuna-Cabello, Maria, Riley, Jennifer, Pont, Caterina, Simeons, Frederick, Stojanovski, Laste, Thomas, John, Thompson, Stephen, Viayna, Elisabet, Fiandor, Jose M, Martin, Julio, Wyatt, Paul G, Miles, Timothy J, Read, Kevin D, Marco, Maria, Gilbert, Ian H
• Format: Article
• Language: English
• Subjects: Animals; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - metabolism; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - therapeutic use; Binding Sites; Cell Line; Drug Design; Drug Evaluation, Preclinical; Half-Life; Humans; Leishmania donovani - drug effects; Leishmania donovani - metabolism; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - parasitology; Mice; Molecular Dynamics Simulation; Proteasome Endopeptidase Complex - chemistry; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - metabolism; Proteasome Inhibitors - pharmacology; Proteasome Inhibitors - therapeutic use; Protein Subunits - chemistry; Protein Subunits - metabolism; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacology; Pyridines - therapeutic use; Solubility; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00047

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series’ structure–activity relationships.