A Covalent BTK Ternary Complex Compatible with Targeted Protein Degradation

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Mar 2

PMID 36864023

Authors

James Schiemer

Andrew Maxwell

Reto Horst

Shenping Liu

Daniel P Uccello

Kris Borzilleri

Nisha Rajamohan

Matthew F Brown

Matthew F Calabrese

Affiliations

Soon will be listed here.

Abstract

Targeted protein degradation using heterobifunctional chimeras holds the potential to expand target space and grow the druggable proteome. Most acutely, this provides an opportunity to target proteins that lack enzymatic activity or have otherwise proven intractable to small molecule inhibition. Limiting this potential, however, is the remaining need to develop a ligand for the target of interest. While a number of challenging proteins have been successfully targeted by covalent ligands, unless this modification affects form or function, it may lack the ability to drive a biological response. Bridging covalent ligand discovery with chimeric degrader design has emerged as a potential mechanism to advance both fields. In this work, we employ a set of biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton's tyrosine kinase. Our results reveal that covalent target modification is fundamentally compatible with the protein degrader mechanism of action.

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References

Zorba A, Nguyen C, Xu Y, Starr J, Borzilleri K, Smith J . Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc Natl Acad Sci U S A. 2018; 115(31):E7285-E7292. PMC: 6077745. DOI: 10.1073/pnas.1803662115. View

Halgren T . Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model. 2009; 49(2):377-89. DOI: 10.1021/ci800324m. View

Xue G, Chen J, Liu L, Zhou D, Zuo Y, Fu T . Protein degradation through covalent inhibitor-based PROTACs. Chem Commun (Camb). 2020; 56(10):1521-1524. DOI: 10.1039/c9cc08238g. View

Buckley D, Raina K, Darricarrere N, Hines J, Gustafson J, Smith I . HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins. ACS Chem Biol. 2015; 10(8):1831-7. PMC: 4629848. DOI: 10.1021/acschembio.5b00442. View

Tinworth C, Lithgow H, Dittus L, Bassi Z, Hughes S, Muelbaier M . PROTAC-Mediated Degradation of Bruton's Tyrosine Kinase Is Inhibited by Covalent Binding. ACS Chem Biol. 2019; 14(3):342-347. DOI: 10.1021/acschembio.8b01094. View

Maher P . Proteasome Assay in Cell Lysates. Bio Protoc. 2016; 4(2). PMC: 4948644. DOI: 10.21769/bioprotoc.1028. View

Palmer 3rd A, Kroenke C, Loria J . Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules. Methods Enzymol. 2001; 339:204-38. DOI: 10.1016/s0076-6879(01)39315-1. View

Rothweiler E, Brennan P, Huber K . Covalent fragment-based ligand screening approaches for identification of novel ubiquitin proteasome system modulators. Biol Chem. 2022; 403(4):391-402. DOI: 10.1515/hsz-2021-0396. View

Dueber E, Schoeffler A, Lingel A, Elliott J, Fedorova A, Giannetti A . Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science. 2011; 334(6054):376-80. DOI: 10.1126/science.1207862. View

10.

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

11.

Zain R, Vihinen M . Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors. Front Immunol. 2021; 12:694853. PMC: 8328433. DOI: 10.3389/fimmu.2021.694853. View

12.

Schiemer J, Horst R, Meng Y, Montgomery J, Xu Y, Feng X . Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes. Nat Chem Biol. 2020; 17(2):152-160. DOI: 10.1038/s41589-020-00686-2. View

13.

Honigberg L, Smith A, Sirisawad M, Verner E, Loury D, Chang B . The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010; 107(29):13075-80. PMC: 2919935. DOI: 10.1073/pnas.1004594107. View

14.

Yu X, Li D, Kottur J, Shen Y, Kim H, Park K . A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models. Sci Transl Med. 2021; 13(613):eabj1578. PMC: 8500670. DOI: 10.1126/scitranslmed.abj1578. View

15.

Condon S, Mitsuuchi Y, Deng Y, LaPorte M, Rippin S, Haimowitz T . Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies. J Med Chem. 2014; 57(9):3666-77. DOI: 10.1021/jm500176w. View

16.

Gabizon R, London N . The rise of covalent proteolysis targeting chimeras. Curr Opin Chem Biol. 2021; 62:24-33. DOI: 10.1016/j.cbpa.2020.12.003. View

17.

Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi A . PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016; 113(26):7124-9. PMC: 4932933. DOI: 10.1073/pnas.1521738113. View

18.

Los G, Encell L, McDougall M, Hartzell D, Karassina N, Zimprich C . HaloTag: a novel protein labeling technology for cell imaging and protein analysis. ACS Chem Biol. 2008; 3(6):373-82. DOI: 10.1021/cb800025k. View

19.

Yuan M, Chu Y, Duan Y . Reversible Covalent PROTACs: Novel and Efficient Targeted Degradation Strategy. Front Chem. 2021; 9:691093. PMC: 8287302. DOI: 10.3389/fchem.2021.691093. View

20.

Pan Z, Scheerens H, Li S, Schultz B, Sprengeler P, Burrill L . Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem. 2006; 2(1):58-61. DOI: 10.1002/cmdc.200600221. View