Genomic discovery of an evolved, genetically programmable modality for selective small-molecule targeting of an intractable protein surface

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and new therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a novel natural product, WDB002, reveals a new therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled-coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of “undruggability” for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus “reprogram” FKBP12 to engage diverse, otherwise “undruggable” target proteins. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analogue may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.