Final Report

1. Project objectives

The overall objective was to screen a Daiichi Sankyo’s new diversity collection to identify progressable hit series for Chagas disease meeting GHIT/DNDi hit criteria. A total of 37,000 proprietary compounds were selected from a new portion of the Daiichi Sankyo Pharma Space Library not previously tested, which was particularly enriched in original and sp³-rich compounds.

2. Project design

The activities were conducted as below.

Step 1: Dispensing of 37,000 compounds from the Daiichi Sankyo Pharma Space Library

Step 2: Single-point T. cruzi screen

Step 3: Dose-response T. cruzi screen

Step 4: T. cruzi hit confirmation and CYP51 inhibition testing

Step 5: Resynthesis of 10 most promising and representative hits

Step 6: T. cruzi hit confirmation in at least two T. cruzi assays following by mechanism of action (MoA) assaying (proteasome inhibition, tRNA synthase inhibition and cytochrome bc1 inhibition)

Step 7: ADME profiling of hit compounds including solubility, metabolic stability in mouse and human microsomes, logD, permeability

Step 8: Data review - new progressable series identified

3. Results, lessons learned

The most promising 58 hits meeting DNDi T. cruzi hit activity criteria were selected following T. cruzi high-throughput screening conducted at IPK. According to the cluster analysis conducted by Daiichi Sankyo, these 58 hit compounds were classified into 22 clusters. All 58 compounds passed quality control criteria. These 58 compounds were tested in T. cruzi and CYP51 inhibition assays at the University of Dundee. As a result, 4 distinct chemical series meeting DNDi T. cruzi hit criteria were identified. A few representatives related to these series were resynthesized. The quinazoline scaffold was deprioritized based on the findings from the NTDs Booster project. The 3 other scaffolds are novel to our Chagas discovery programs and confirmed well for T. cruzi activity in 3 different T. cruzi assay systems. All compounds were profiled for solubility, metabolic stability, logD, permeability, and plasma protein binding, and data indicated further improvements in physicochemical properties are required via derivatization. This work will be conducted by Daiichi Sankyo and DNDi over the next few months outside GHIT funding support in parallel to testing in additional MoA assays.