Abstract
Diversity-oriented synthesis (DOS)is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting in the elucidation of novel biological mechanisms. In parallel to the development of DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient screening strategy to identify protein binders. Despite recent advancements in this field, most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here, we describe the design, synthesis, and validation experiments performed for a 3.7 million-member DEL, generated using diverse skeleton architectures with varying exit vectors, derived from DOS, to achieve structural diversity beyond what is possible by varying appendages alone. We will make this DEL available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.
Competing Interest Statement
CJG is a shareholder in and employee of Kisbee Therapeutics. C.W.C. is an advisor to Anagenex. P.A.C. is an advisor to nference, Inc., Pfizer, Inc., and Belharra Therapeutics. B.M. is a scientific advisor to Magnet Biomedicine. S.L.S. is a shareholder and serves on the Board of Directors of Jnana Therapeutics and Kojin Therapeutics; is a shareholder and advises Kisbee Therapeutics, Belharra Therapeutics, Magnet Biomedicine, Exo Therapeutics, and Eikonizo Therapeutics; advises Vividian Therapeutics, Eisai Co., Ltd., Ono Pharma Foundation, F-Prime Capital Partners, and the Genomics Institute of the Novartis Research Foundation; and is a Novartis Faculty Scholar.
Footnotes
Updated entire text for clarity and to add relevant supporting details and references. Updated formatting of figures for clarity.
