High-throughput chemistry has dramatically accelerated the design-make-test cycle of optimization. Advancements in synthetic methods, analytical instrumentation, and informatics have enabled miniaturization, increased library size, and decreased cycle times. Examples illustrating the utility of these high throughput workflows will be presented, spanning a diverse range of optimizations in a medicinal chemistry context. Highlights of iterative analog library optimizations will be discussed from a number of drug discovery projects.<br/><br/>In addition, development of reaction conditions enabling the synthesis of chemical biology probes will be described. Access to high quality photoaffinity probe molecules is often constrained by synthetic limitations related to diazirine installation. To test whether advances in modern cross-coupling catalysis might enable efficient cross couplings tolerant of the diazirine moiety, a fragment-based screening approach was employed. A model coupling reaction was screened under various conditions in the presence of an aromatic diazirine fragment. This screen identified reaction conditions that gave good yields of product while minimally perturbing the diazirine reporter fragment. These conditions were found to be highly scalable and exhibited broad scope when applied to a chemistry informer library of pharmaceutically relevant aryl boron pinacol esters.<br/><br/>Lastly, a platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) will be presented. This method uses a direct-to-biology (D2B) approach, with a focus on investigating linker effects. A large number of linker analogs – varying length, polarity, and rigidity – were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure activity relationships for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity. Unexpected aspects of linker SAR were discovered, consistent with literature reports on “linkerology”, and the method dramatically speeds up empirical optimization.

High-throughput chemistry accelerates the optimization of small molecule therapeutics, chemical biology probes, and protein degraders

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.