Fragment-based drug discovery (FBDD) is now widely recognized as a complementary approach to high-throughput screening for developing drug-like molecules. The FDA-approved drugs vemerafanib (metastatic melanoma), venetoclax (chronic lymphocytic leukemia), and ribocilcib (ER+/HER- breast cancer) originated from FBDD platforms; dozens more are currently under clinical evaluation. Notwithstanding these successes, implementing FBDD presents a distinct set of challenges. Fragments are usually weak binders and conducting fragment library screens at the high concentrations needed to detect binding can yield a high proportion of false positives that are difficult to distinguish from true hits. Perhaps more importantly, the chemical diversity of typical fragment libraries has been strongly biased to sp2-rich heteroaromatic compounds; this necessarily biases the putative initial hits, and so may preclude the identification of weak but potentially optimizable binders for many disease targets. We are using the synthetic guiding principle of systematic chemical diversity (SCD) to construct sp3-enriched fragment scaffold families that address both of these challenges. Enantiopure cohorts of regoisomers, relative and absolute stereoisomers, and appendage diversification elements are produced in a matrix fashion. The fragment shapes and the vectors at which they present appendages differ substantially from typical fragment libraries and are quite varied across a cohort. Screening systematically related molecules against a target provides SAR data that enables hit identification with high confidence since a true hit should bind much tighter than its enantiomer. Moreover, comparing the differences between hits and non-hits yields information that is immediately actionable toward fragment optimization. Because the chemical space represented by systematically sampling the regioisomeric, diastereomeric, enantiomeric and appendage relationships within a fragment collection is distinct from the space sampled by typical sp2-biased fragment screens, we expect that our libraries will bind to a distinct (though sometimes overlapping) set of protein pockets and disease targets. The lecture will describe the application of fragment-based SCD toward several high-value biological disease targets.

Using systematic chemical diversity to enable fragment-based drug discovery

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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