Targeted Kinase Degradation Via the KLHDC2 Ubiquitin E3 Ligase

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2023 Aug 11

PMID 37567174

Authors

Younghoon Kim

Pooreum Seo

Eunhye Jeon

Inchul You

Kyubin Hwang

Namkyoung Kim

Jason Tse

Juhyeon Bae

Ha-Soon Choi

Stephen M Hinshaw

Nathanael S Gray

Taebo Sim

Affiliations

Soon will be listed here.

Abstract

Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves an induced proximity between the cellular ubiquitin-conjugation machinery and a target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-like homology domain-containing protein 2 (KLHDC2), a substrate adapter protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of peptide-based ligands useful for this purpose.

Citing Articles

Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2.

Scott D, Dharuman S, Griffith E, Chai S, Ronnebaum J, King M Nat Commun. 2024; 15(1):8829.

PMID: 39396041 PMC: 11470957. DOI: 10.1038/s41467-024-52966-3.

PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network.

Huber A, Lin W, Poudel S, Miller D, Chen T Structure. 2024; 32(12):2352-2363.e8.

PMID: 39389062 PMC: 11647748. DOI: 10.1016/j.str.2024.09.016.

An artificial intelligence accelerated virtual screening platform for drug discovery.

Zhou G, Rusnac D, Park H, Canzani D, Nguyen H, Stewart L Nat Commun. 2024; 15(1):7761.

PMID: 39237523 PMC: 11377542. DOI: 10.1038/s41467-024-52061-7.

Applications of protein ubiquitylation and deubiquitylation in drug discovery.

Chen Y, Xue H, Jin J J Biol Chem. 2024; 300(5):107264.

PMID: 38582446 PMC: 11087986. DOI: 10.1016/j.jbc.2024.107264.

The herpesvirus UL49.5 protein hijacks a cellular C-degron pathway to drive TAP transporter degradation.

Wachalska M, Riepe C, Slusarz M, Graul M, Borowski L, Qiao W Proc Natl Acad Sci U S A. 2024; 121(11):e2309841121.

PMID: 38442151 PMC: 10945846. DOI: 10.1073/pnas.2309841121.

References

Donovan K, Ferguson F, Bushman J, Eleuteri N, Bhunia D, Ryu S . Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development. Cell. 2020; 183(6):1714-1731.e10. PMC: 10294644. DOI: 10.1016/j.cell.2020.10.038. View

Bekes M, Langley D, Crews C . PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022; 21(3):181-200. PMC: 8765495. DOI: 10.1038/s41573-021-00371-6. View

Yeh C, Huang W, Hsu P, Yeh K, Wang L, Hsu P . The C-degron pathway eliminates mislocalized proteins and products of deubiquitinating enzymes. EMBO J. 2021; 40(7):e105846. PMC: 8013793. DOI: 10.15252/embj.2020105846. View

Dolle A, Adhikari B, Kramer A, Weckesser J, Berner N, Berger L . Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders. J Med Chem. 2021; 64(15):10682-10710. DOI: 10.1021/acs.jmedchem.1c00146. View

Schneekloth Jr J, Fonseca F, Koldobskiy M, Mandal A, Deshaies R, Sakamoto K . Chemical genetic control of protein levels: selective in vivo targeted degradation. J Am Chem Soc. 2004; 126(12):3748-54. DOI: 10.1021/ja039025z. View

Soucy T, Smith P, Milhollen M, Berger A, Gavin J, Adhikari S . An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009; 458(7239):732-6. DOI: 10.1038/nature07884. View

Davies T, Wixted W, Coyle J, Griffiths-Jones C, Hearn K, McMenamin R . Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery. J Med Chem. 2016; 59(8):3991-4006. DOI: 10.1021/acs.jmedchem.6b00228. View

Li Z, Pinch B, Olson C, Donovan K, Nowak R, Mills C . Development and Characterization of a Wee1 Kinase Degrader. Cell Chem Biol. 2019; 27(1):57-65.e9. PMC: 6980656. DOI: 10.1016/j.chembiol.2019.10.013. View

Rusnac D, Lin H, Canzani D, Tien K, Hinds T, Tsue A . Recognition of the Diglycine C-End Degron by CRL2 Ubiquitin Ligase. Mol Cell. 2018; 72(5):813-822.e4. PMC: 6294321. DOI: 10.1016/j.molcel.2018.10.021. View

10.

Schwinn M, Machleidt T, Zimmerman K, Eggers C, Dixon A, Hurst R . CRISPR-Mediated Tagging of Endogenous Proteins with a Luminescent Peptide. ACS Chem Biol. 2017; 13(2):467-474. DOI: 10.1021/acschembio.7b00549. View

11.

Lin H, Yeh C, Chen Y, Lee T, Hsieh P, Rusnac D . C-Terminal End-Directed Protein Elimination by CRL2 Ubiquitin Ligases. Mol Cell. 2018; 70(4):602-613.e3. PMC: 6145449. DOI: 10.1016/j.molcel.2018.04.006. View

12.

Ishida T, Ciulli A . E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones. SLAS Discov. 2020; 26(4):484-502. PMC: 8013866. DOI: 10.1177/2472555220965528. View

13.

Machleidt T, Woodroofe C, Schwinn M, Mendez J, Robers M, Zimmerman K . NanoBRET--A Novel BRET Platform for the Analysis of Protein-Protein Interactions. ACS Chem Biol. 2015; 10(8):1797-804. DOI: 10.1021/acschembio.5b00143. View

14.

Cho H, Shin I, Yoon H, Jeon E, Lee J, Kim Y . Identification of Thieno[3,2-]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3. J Med Chem. 2021; 64(16):11934-11957. DOI: 10.1021/acs.jmedchem.1c00459. View

15.

Luo X, Archibeque I, Dellamaggiore K, Smither K, Homann O, Lipford J . Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases. iScience. 2022; 25(3):103985. PMC: 8919295. DOI: 10.1016/j.isci.2022.103985. View

16.

Smith B, Wang S, Jaime-Figueroa S, Harbin A, Wang J, Hamman B . Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat Commun. 2019; 10(1):131. PMC: 6328587. DOI: 10.1038/s41467-018-08027-7. View

17.

Zhang L, Riley-Gillis B, Vijay P, Shen Y . Acquired Resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) Caused by Genomic Alterations in Core Components of E3 Ligase Complexes. Mol Cancer Ther. 2019; 18(7):1302-1311. DOI: 10.1158/1535-7163.MCT-18-1129. View

18.

Scott D, King M, Baek K, Gee C, Kalathur R, Li J . E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity. Mol Cell. 2023; 83(5):770-786.e9. PMC: 10080726. DOI: 10.1016/j.molcel.2023.01.019. View

19.

Nowak R, DeAngelo S, Buckley D, He Z, Donovan K, An J . Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat Chem Biol. 2018; 14(7):706-714. PMC: 6202246. DOI: 10.1038/s41589-018-0055-y. View

20.

Jan M, Sperling A, Ebert B . Cancer therapies based on targeted protein degradation - lessons learned with lenalidomide. Nat Rev Clin Oncol. 2021; 18(7):401-417. PMC: 8903027. DOI: 10.1038/s41571-021-00479-z. View