A scaffold-hopping strategy on a series of proteasome inhibitors which led to a preclinical candidate for the treatment of visceral leishmaniasis

Michael Thomas, Stephen Brand, Manu De Rycker, Fabio Zuccotto, Iva Lukac, Peter 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 Martín, Paul G. WyattTimothy J. Miles, Kevin D. Read, Maria Marco, Ian H. Gilbert

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Abstract

There is urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily on 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 optimised to give a compound with in vivo efficacy which was hampered by poor solubility and genotoxicity. 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 utilised, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modelling of the different scaffolds into the cryo-EM structure and the impact this has on our understanding of the series Structure Activity Relationships.
Original languageEnglish
Number of pages26
JournalJournal of Medicinal Chemistry
Early online date27 Apr 2021
DOIs
Publication statusE-pub ahead of print - 27 Apr 2021

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