The European Lead Factory: Results from a decade of collaborative, public-private, drug discovery programs.

The European Lead Factory (ELF) is a consortium of universities and small and medium-sized enterprises (SMEs) dedicated to drug discovery, and the pharmaceutical industry. This unprecedented consortium provides high-throughput screening, triage, and hit validation, including to non-consortium members. The ELF library was created through a novel compound-sharing model between nine pharmaceutical companies and expanded through library synthesis by chemistry-specialized SMEs. The library has been screened against ∼270 different targets and 15 phenotypic assays, and hits have been developed to form the basis of patents and spin-off companies. Here, we review the outcome of screening campaigns of the ELF, including the performance and physicochemical properties of the library, identification of possible frequent hitter compounds, and the effectiveness of the compound-sharing model.

Identification of Compounds Protecting Pancreatic Islets against Oxidative Stress using a 3D Pseudoislet Screening Platform.

Oxidative stress leads to a lower success rate of clinical islet transplantation. Here, FDA-approved compounds are screened for their potential to decrease oxidative stress and to protect or enhance pancreatic islet viability and function. Studies are performed on in vitro "pseudoislet" spheroids, which are pre-incubated with 1280 different compounds and subjected to oxidative stress. Cell viability and oxidative stress levels are determined using a high-throughput fluorescence microscopy pipeline. Initial screening on cell viability results in 59 candidates. The top ten candidates are subsequently screened for their potential to decrease induced oxidative stress, and eight compounds efficient reduction of induced oxidative stress in both alpha and beta cells by 25-50%. After further characterization, the compound sulfisoxazole is found to be the most capable of reducing oxidative stress, also at short pre-incubation times, which is validated in primary human islets, where low oxidative stress levels and islet function are maintained. This study shows an effective screening strategy with 3D cell aggregates based on cell viability and oxidative stress, which leads to the discovery of several compounds with antioxidant capacity. The top candidate, sulfisoxazole is effective after a 30 min pre-incubation, maintains baseline islet function, and may help alleviate oxidative stress in pancreatic islets.

Hit Discovery for Public Target Programs in the European Lead Factory: Experiences and Output from Assay Development and Ultra-High-Throughput Screening.

The European Lead Factory (ELF) consortium provides European academics and small and medium enterprises access to ~0.5 million unique compounds, a state-of-the-art ultra-high-throughput screening (u-HTS) platform, and industrial early drug discovery (DD) expertise with the aim of delivering innovative DD starting points. From 2013 to 2018, 154 proposals for eight target classes in seven therapeutic areas were submitted to the ELF consortium, 88 of which were accepted by the selection committee. During this period, 76 primary assays based on seven different readout technologies were optimized and mainly miniaturized to 1536-well plates. In total, 72 u-HTS campaigns were carried out, and follow-up work including hit triage through orthogonal, deselection, selectivity, and biophysical assays were finalized. This ambitious project showed that besides the quality of the compound library and the primary assay, the success of centralized u-HTS of large compound libraries across many target classes, various assay types, and different readout technologies is also largely dependent on the capacity and flexibility of the automation on one hand and the hit-triaging phase on the other, particularly because of undesired compound-assay interference. Thus far, the delivered hit lists from the ELF consortium have resulted in spinoffs, patents, in vivo proof of concepts, preclinical development programs, peer-reviewed publications, PhD theses, and much more, demonstrating early success indications.