Through collaborative hit-to-lead projects, identify new leads with activity in animal models of disease and the potential for further optimization
current phase of drug development
updated 15 Feb 2023
Hit-to-lead is a dynamic phase in the drug discovery process in which small molecule hits from high-throughput screening are evaluated and undergo optimization to identify promising lead compounds.
The process of hit-to-lead optimization is ongoing, with multiple series being progressed based on outputs of the screening programme. A variety of hit-to-lead mechanisms and exploration strategies are being used to progress towards in vivo proof-of-concept studies in pre-clinical efficacy models of Chagas disease.
The NTD Drug Discovery Booster is a related project conducting early-stage drug discovery to identify new treatments for leishmaniasis and Chagas disease.
Over 20 new lead chemical series identified in 2021 progressed through the stages of hit identification in 2022 – including hit confirmation, extended ADME profiling, and in vivo proof-of-concept studies. The lead chemical series originated from several sources, including commercial libraries, natural products, and external partners. To avoid late-stage attrition linked to the identification of unwanted or already explored mechanisms of action, all candidate compound series are now tested against panels of known targets or resistant mutants at an early stage of the hit-to-lead process, if not before.
Over 25 new lead chemical series identified in 2020 are progressing through the stages of hit identification – including hit confirmation, elucidation of the mechanism of action, and proof-of-concept studies – leading up to hit nomination.
Approximately 15 distinct series from various origins were progressed.
DNDi has continued its efforts in screening chemically diverse libraries to replenish the discovery pipeline. Confirmed new hits are continuously feeding the hit-to-lead pipeline. In 2019, a new consortium was established in collaboration with University of Campinas and University of Sao Paulo in Brazil. Through a team of scientists working in a global network, PITE (Research Partnership for Technological Innovation) aims to deliver a high-quality pre-clinical candidate compound that could become a new treatment for Chagas disease.
DNDi has continued its efforts in screening chemically diverse libraries for identification and confirmation of new hits that could progress and feed the hit-to-lead pipeline. In 2018, a new partnership was established with the Drug Discovery Unit from Dundee University in Scotland and GSK to jointly characterize and progress new promising hits.
A new discovery cascade has been implemented comprising new in vitro and in vivo. If promising activity is demonstrated, the identified series would then be advanced into full lead optimization programmes.
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