RESUMEN
The three human SNM1 metallo-ß-lactamase fold nucleases (SNM1A-C) play key roles in DNA damage repair and in maintaining telomere integrity. Genetic studies indicate that they are attractive targets for cancer treatment and to potentiate chemo- and radiation-therapy. A high-throughput screen for SNM1A inhibitors identified diverse pharmacophores, some of which were shown by crystallography to coordinate to the di-metal ion centre at the SNM1A active site. Structure and turnover assay-guided optimization enabled the identification of potent quinazoline-hydroxamic acid containing inhibitors, which bind in a manner where the hydroxamic acid displaces the hydrolytic water and the quinazoline ring occupies a substrate nucleobase binding site. Cellular assays reveal that SNM1A inhibitors cause sensitisation to, and defects in the resolution of, cisplatin-induced DNA damage, validating the tractability of MBL fold nucleases as cancer drug targets.
RESUMEN
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.