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

Michael Thomas, Stephen Brand, Manu De Rycker, Fabio Zuccotto, Iva Lukac, Peter G. Dodd, Eun-Jung Ko, Sujatha Manthri, Kate McGonagle, Maria Osuna-Cabello, Jennifer Riley, Caterina Pont, Frederick Simeons, Laste Stojanovski, John Thomas, Stephen Thompson, Elisabet Viayna, Jose M. Fiandor*, Julio Martin*, Paul G. Wyatt, Timothy J. Miles*, Kevin D. Read, Maria Marco*, and Ian H. Gilbert.

*Global Health R&D, GlaxoSmithKline, Tres Cantos 28760, Spain

J. Med. Chem. 2021, 64, 9, 5905–5930 27 April 2021


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.