Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

Significance This manuscript reports on a member of the FK506/rapamycin family, WDB002, and the realization that FKBP-mediated recognition is a genetically programmable modality that enables engagement of topologically flat targets. FKBP-mediated recognition is thus nature’s strategy for drugging the “undruggable.” The surface of FKBP engages three completely unrelated targets—calcineurin, MTOR, and CEP250—with high-target affinity and specificity, using different constellations of amino acid residues. Target specificity is determined solely by the “variable domain” of the bound small molecule alone, suggesting the modality might be generalizable to other undruggable targets through variable domain engineering. Finally, since WDB002 targets CEP250, it may be a promising starting point for developing a treatment for COVID-19.