Chagas Hit-to-lead

DNDi reorganized its early-stage Chagas discovery portfolio at the beginning of 2025 to streamline processes and leverage resources to increase efficiency while reducing costs and turnaround time. Multiple lead optimization consortia were brought together into a single global hit-to-lead and lead optimization consortium focused on Chagas disease. This complementary network streamlines the hit-to-lead journey, encourages knowledge sharing, reduces differences in data across labs, and improves oversight of the global portfolio – ultimately increasing the chances of finding a suitable candidate. Within this framework, a diverse set of chemical series have been de-risked for unwanted mechanisms and are being advanced with encouraging results.

Several chemical scaffolds continue to be profiled and optimized mainly via phenotypic hit-to-lead campaigns. One series from the early-stage portfolio achieved lead criteria and was progressed to the lead optimization stage (Series-5824) in collaboration with Mitsubishi Tanabe, and several others were stopped due to difficulties in optimization.

Meanwhile, together with our discovery partners, we continued exploring new technologies, such as AI and machine learning, and alternative approaches such as target-based drug discovery to speed up compound progression and unlock new opportunities to identify novel candidates.

Discovery efforts prioritized the identification of high-quality compounds that show novelty in terms of both chemical structure and mode of action. Several new hit-to-lead projects started in 2023 after a systematic hit assessment following reanalysis of hits originating from commercial compound libraries.

In parallel, ongoing hit-to-lead campaigns continued to progress via partnerships around the globe. For at least two chemical series, advanced leads showed promising efficacy in in vivo models – an important milestone for go/no-go decisions on advancement to full lead optimization programmes – with in vitro data pointing to a novel mode of action.

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.