Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.

Over the past decade, DNA-encoded libraries (DELs) have emerged as a leading platform for small molecule drug discovery among pharmaceutical companies, biotech companies and academic drug hunters alike. This revolutionary technology has tremendous potential that is yet to be fully realized, as the exploration of therapeutically relevant chemical space is fueled by the ever-expanding repertoire of DNA-compatible reactions used to construct the libraries. Advances in direct coupling reactions, like photo-catalytic cross couplings, unique cyclizations such as the formation of 1,2,4-oxadiazoles, and new functional group transformations are valuable contributions to the DEL reaction toolkit, and indicate where future reaction development efforts should focus in order to maximize the productivity of DELs.

Synthesis of the C-2-symmetric, non-adjacent bis(tetrahydrofuran) core of squamostanin C in seven steps and 24% overall yield from (R,R)-1,5-hexadiene-3,4-diol is reported. Silicon-tethered, size-selective triple ring-closing metathesis of an acyclic hexaene is employed for assembly of the central 1,4-diol unit and concurrent chain extension via lactone formation. Stereoselective construction of both tetrahydrofuran rings is achieved in one step through the use of two-directional Mukaiyama aerobic alkenol cyclization. (C) 2019 Elsevier Ltd. All rights reserved.