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

Autor:	Shigdel UK; Warp Drive Bio, Inc., Redwood City, CA 94063., Lee SJ; Warp Drive Bio, Inc., Redwood City, CA 94063., Sowa ME; Warp Drive Bio, Inc., Redwood City, CA 94063., Bowman BR; Warp Drive Bio, Inc., Redwood City, CA 94063., Robison K; Warp Drive Bio, Inc., Redwood City, CA 94063., Zhou M; Warp Drive Bio, Inc., Redwood City, CA 94063., Pua KH; Warp Drive Bio, Inc., Redwood City, CA 94063., Stiles DT; Warp Drive Bio, Inc., Redwood City, CA 94063., Blodgett JAV; Warp Drive Bio, Inc., Redwood City, CA 94063., Udwary DW; Warp Drive Bio, Inc., Redwood City, CA 94063., Rajczewski AT; Warp Drive Bio, Inc., Redwood City, CA 94063., Mann AS; Warp Drive Bio, Inc., Redwood City, CA 94063., Mostafavi S; Warp Drive Bio, Inc., Redwood City, CA 94063., Hardy T; Department of Molecular and Cell Biology, University of Leicester, LE1 7RH Leicester, United Kingdom., Arya S; Department of Molecular and Cell Biology, University of Leicester, LE1 7RH Leicester, United Kingdom., Weng Z; Warp Drive Bio, Inc., Redwood City, CA 94063., Stewart M; Warp Drive Bio, Inc., Redwood City, CA 94063., Kenyon K; Warp Drive Bio, Inc., Redwood City, CA 94063., Morgenstern JP; Warp Drive Bio, Inc., Redwood City, CA 94063., Pan E; Warp Drive Bio, Inc., Redwood City, CA 94063., Gray DC; Warp Drive Bio, Inc., Redwood City, CA 94063., Pollock RM; Warp Drive Bio, Inc., Redwood City, CA 94063., Fry AM; Department of Molecular and Cell Biology, University of Leicester, LE1 7RH Leicester, United Kingdom., Klausner RD; Lyell Immunopharma, South San Francisco, CA 94080; klausner.rick@gmail.com gregory_verdine@harvard.edu., Townson SA; Warp Drive Bio, Inc., Redwood City, CA 94063., Verdine GL; Warp Drive Bio, Inc., Redwood City, CA 94063; klausner.rick@gmail.com gregory_verdine@harvard.edu.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jul 21; Vol. 117 (29), pp. 17195-17203. Date of Electronic Publication: 2020 Jun 30.
DOI:	10.1073/pnas.2006560117
Abstrakt:	The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a 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" targets. 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 analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12. Competing Interests: Competing interest statement: U.K.S., S.-J.L., M.E.S., B.R.B., K.R., M.Z., K.H.P., D.T.S., J.A.V.B., D.W.U., A.T.R., A.S.M., S.M., Z.W., M.S., K.K., J.P.M., E.P., D.C.G., R.M.P., S.A.T., and G.L.V. were employees of Warp Drive Bio, which has since become a wholly owned subsidiary of Revolution Medicines, Inc. G.L.V., R.D.K., and B.R.B. are minority shareholders in Revolution Medicines, Inc. R.D.K. is an employee of Lyell Immunopharma. U.K.S. is an employee of LifeMine Therapeutics. S.-J.L. is an employee of Beam Therapeutics. M.E.S. is an employee of C4 Therapeutics. B.R.B. is an employee of Inzen Therapeutics. K.R., D.T.S., K.K., J.P.M., and D.C.G. are employees of Ginko Bioworks. M.Z. is an employee of Kronos Bio. K.H.P. is an employee of A*STAR. A.S.M. is an employee of Agios Pharmaceuticals. S.M. is an employee of Morphic Therapeutic. Z.W. is an employee of Blueprint Medicines. M.S. is an employee of Bristol-Myers Squibb. E.P. is an employee of Amgen. S.A.T. is an employee of Kymera Therapeutics. G.L.V. is an employee of FOG Pharmaceuticals, Inc. and LifeMine Therapeutics. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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