Crystal structures of DCAF1-PROTAC-WDR5 ternary complexes provide insight into DCAF1 substrate specificity

  • Nat Commun. 2024 Nov 23;15(1):10165. doi: 10.1038/s41467-024-54500-x.
Mark F Mabanglo  #  1 ,  Brian Wilson  #  1 ,  Mahmoud Noureldin  #  1 ,  Serah W Kimani  2 ,  Ahmed Mamai  1 ,  Chiara Krausser  1 ,  Héctor González-Álvarez  1  3 ,  Smriti Srivastava  1 ,  Mohammed Mohammed  1 ,  Laurent Hoffer  1 ,  Manuel Chan  1 ,  Jamie Avrumutsoae  1 ,  Alice Shi Ming Li  1  3 ,  Taraneh Hajian  1 ,  Sarah Tucker  1 ,  Stuart Green  2 ,  Magdalena Szewczyk  2 ,  Dalia Barsyte-Lovejoy  2  3 ,  Vijayaratnam Santhakumar  2 ,  Suzanne Ackloo  2 ,  Peter Loppnau  2 ,  Yanjun Li  2 ,  Almagul Seitova  2 ,  Taira Kiyota  1 ,  Jue George Wang  1 ,  Gilbert G Privé  4 ,  Douglas A Kuntz  4 ,  Bhashant Patel  5 ,  Vaibhavi Rathod  5 ,  Anand Vala  5 ,  Bhimsen Rout  5 ,  Ahmed Aman  1  6 ,  Gennady Poda  1  6 ,  David Uehling  1 ,  Jailall Ramnauth  1 ,  Levon Halabelian  2  3 ,  Richard Marcellus  1 ,  Rima Al-Awar  7  8  9 ,  Masoud Vedadi  10  11
Affiliations
  • 1. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • 2. Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
  • 3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
  • 4. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 5. Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Ahmedabad, Gujarat, India.
  • 6. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
  • 7. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada. [email protected].
  • 8. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. [email protected].
  • 9. Department of Chemistry, University of Toronto, Toronto, ON, Canada. [email protected].
  • 10. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada. [email protected].
  • 11. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. [email protected].
  • # Contributed equally.
PMID: 39580491 DOI: 10.1038/s41467-024-54500-x
Abstract

Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 Ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs. We recently developed potent ligands for DCAF1, a substrate receptor of EDVP and CUL4 E3 Ligases. Here, we focus on DCAF1 toward the development of PROTACs for WDR5, a drug target in various cancers. We report four DCAF1-based PROTACs with endogenous and exogenous WDR5 degradation effects and high-resolution crystal structures of the ternary complexes of DCAF1-PROTAC-WDR5. The structures reveal detailed insights into the interaction of DCAF1 with various WDR5-PROTACs, indicating a significant role of DCAF1 loops in providing needed surface plasticity, and reflecting the mechanism by which DCAF1 functions as a substrate receptor for E3 Ligases with diverse sets of substrates.

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