Abstract
Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.
| Original language | English |
|---|---|
| Pages (from-to) | 1714-1731.e10 |
| Journal | Cell |
| Volume | 183 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2020 Dec 10 |
Bibliographical note
Funding Information:We thank Dennis L. Buckley for providing the following compound samples: DB-03-291, ImatinIMiD-2, ImatinIMiD-5, dRAF-3, dFLT-2, dAURK-4, and dAbl-2. We also thank Lyn H. Jones, Milka Kostic, and Dennis L. Buckley for critical reading of the manuscript. This work was supported by the NIH ( R01CA214608 to E.S.F., R01CA218278 to E.S.F. and N.S.G., and U24-DK116204 to F.M.F. and N.S.G.). E.S.F. is a Damon Runyon-Rachleff Innovator ( DRR-50-18 ). L.T. and K.S. were supported by the China National Natural Science Foundation ( 21778066 ) and the Natural Science Foundation of Shanghai ( 18JC1420500 ). T.B.S. was supported by Korea Institute of Science and Technology ( 2E29260 ), the KU-KIST Graduate School of Converging Science and Technology Program , and Support for Candidate Development Program ( NRF-2016M3A9B5940991 ) of the National Research Foundation of Korea , funded by the Ministry of Science and ICT .
Funding Information:
We thank Dennis L. Buckley for providing the following compound samples: DB-03-291, ImatinIMiD-2, ImatinIMiD-5, dRAF-3, dFLT-2, dAURK-4, and dAbl-2. We also thank Lyn H. Jones, Milka Kostic, and Dennis L. Buckley for critical reading of the manuscript. This work was supported by the NIH (R01CA214608 to E.S.F. R01CA218278 to E.S.F. and N.S.G. and U24-DK116204 to F.M.F. and N.S.G.). E.S.F. is a Damon Runyon-Rachleff Innovator (DRR-50-18). L.T. and K.S. were supported by the China National Natural Science Foundation (21778066) and the Natural Science Foundation of Shanghai (18JC1420500). T.B.S. was supported by Korea Institute of Science and Technology (2E29260), the KU-KIST Graduate School of Converging Science and Technology Program, and Support for Candidate Development Program (NRF-2016M3A9B5940991) of the National Research Foundation of Korea, funded by the Ministry of Science and ICT. K.A.D. conceived the study; designed, performed, and supervised experiments; analyzed data; interpreted results; and wrote the manuscript. F.M.F. conceived the study; designed experiments; designed, synthesized, and supervised compound synthesis; analyzed data; interpreted results; and wrote the manuscript. J.W.B. performed the RNA-seq experiment, wrote analysis code, and analyzed data. N.A.E. performed proteomics experiments. H.Y. performed cellular engagement experiments. D.B. S.R. L.T. K.S. X.L. D.B. B.J. J.W. M.H. I.Y. M.T. Y.L. J.H. Z.L. T.D.M. B.G. W.H. Y.N. S.S. H.C. and I.S. synthesized and provided molecules. M.P.A. performed immunoblot analysis and viability studies. I.M.G. provided biological data. M.W.M. performed cell treatments. J.C. provided cheminformatics expertise. S.J.B. designed and provided molecules. T.S. designed and provided molecules. N.S.G. and E.S.F. conceived the study, interpreted results, and supervised and funded the study. All authors read, edited, and approved the final manuscript. N.S.G. is a founder, science advisory board (SAB) member, and equity holder in Gatekeeper, Syros, Petra, C4, B2S, Aduro, Jengu, and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield, and Sanofi. E.S.F. is a founder, science advisory board member, and equity holder in Civetta, Jengu (board member), and Neomorph, an equity holder in C4, and a consultant to Astellas, Novartis, Deerfield, and EcoR1. The Fischer lab receives or has received research funding from Novartis, Astellas, and Deerfield. K.A.D. F.M.F. J.W.B. T.S. E.S.F. and N.S.G. are inventors on a patent application relating to this work, owned by DFCI.
Publisher Copyright:
© 2020 Elsevier Inc.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)