Delineating the role of cooperativity in the design of potent PROTACs for BTK
- 31 July 2018
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 115 (31), E7285-E7292
- https://doi.org/10.1073/pnas.1803662115
Abstract
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.Keywords
This publication has 52 references indexed in Scilit:
- Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblonJournal of Biological Chemistry, 2018
- BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic LeukemiaJournal of Clinical Oncology, 2017
- NuRD–ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombinationNature Structural & Molecular Biology, 2014
- Ibrutinib in B-cell LymphomasCurrent Treatment Options in Oncology, 2014
- Selective Inhibition of BTK Prevents Murine Lupus and Antibody-Mediated GlomerulonephritisPublished by The American Association of Immunologists ,2013
- Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell LymphomaNew England Journal of Medicine, 2013
- A Comprehensive Mathematical Model for Three-Body Binding EquilibriaJournal of the American Chemical Society, 2013
- The Molecular Basis of CRL4DDB2/CSA Ubiquitin Ligase Architecture, Targeting, and ActivationCell, 2011
- A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardationNeurology, 2004
- Structure of a β-TrCP1-Skp1-β-Catenin ComplexMolecular Cell, 2003