OICR-41103 as a chemical probe for the DCAF1 WD40 domain

  • Commun Biol. 2025 Jul 19;8(1):1076. doi: 10.1038/s42003-025-08491-0.
Serah W Kimani  #  1 ,  Mahmoud Noureldin  #  2  3 ,  Brian Wilson  #  2 ,  Laurent Hoffer  2 ,  Stuart R Green  1 ,  Magdalena M Szewczyk  1 ,  Héctor González-Álvarez  2  3 ,  Mohammed Mohammed  2 ,  Manuel Chan  2 ,  Chiara Krausser  2 ,  Alice Shi Ming Li  2  3 ,  Taraneh Hajian  2 ,  Sarah Tucker  2 ,  Dhananjay Joshi  2 ,  Punit Saraon  2 ,  Brigitte Thériault  2 ,  Ji Sup Kim  2 ,  Vijayaratnam Santhakumar  1 ,  Peter Loppnau  1 ,  Yanjun Li  1 ,  Almagul Seitova  1 ,  Aiping Dong  1 ,  Taira Kiyota  2 ,  Tobias Hammann  4 ,  Paul Gehrtz  4 ,  Bhashant Patel  5 ,  Vaibhavi Rathod  5 ,  Anand Vala  5 ,  Bhimsen Rout  5 ,  Paras Jagodra  5 ,  Peter J Brown  6 ,  Ahmed Aman  2  7 ,  Jailall Ramnauth  2 ,  Gennady Poda  2  7 ,  David Uehling  2 ,  Cheryl H Arrowsmith  1  8  9 ,  Dalia Barsyte-Lovejoy  1  3 ,  Richard Marcellus  2 ,  Suzanne Ackloo  1 ,  Ahmed Mamai  2 ,  Rima Al-Awar  10  11  12 ,  Levon Halabelian  13  14
Affiliations
  • 1. Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
  • 2. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • 3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
  • 4. Medicinal Chemistry, Global Research & Development, Merck Healthcare KGaA, Darmstadt, Germany.
  • 5. Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Ahmedabad, Gujarat, India.
  • 6. Structural Genomics Consortium, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 7. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
  • 8. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 9. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • 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].
  • 12. Department of Chemistry, University of Toronto, Toronto, ON, Canada. [email protected].
  • 13. Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada. [email protected].
  • 14. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. [email protected].
  • # Contributed equally.
PMID: 40683980 DOI: 10.1038/s42003-025-08491-0
Abstract

Human DCAF1 is a multidomain protein that plays a critical role in protein homeostasis. Its WDR domain functions as a substrate recruitment module for RING-type CRL4 and HECT family EDVP E3 ubiquitin ligases, enabling the ubiquitination and proteasomal degradation of specific substrates. DCAF1's activity has been implicated in cell proliferation and is documented to promote tumorigenesis. Additionally, the DCAF1 WDR domain is hijacked by lentiviral accessory proteins to induce the degradation of host Antiviral factors, such as SAMHD1 and UNG2. These diverse roles make DCAF1 an attractive target for therapeutic development in oncology and Antiviral strategies. It is also a promising candidate for use in targeted protein degradation. We previously reported a novel ligand, OICR-8268, that targets the DCAF1 WDR domain. In this study, we present the development of OICR-41103, a potent, selective, and cell-active small molecule chemical probe for DCAF1, derived from OICR-8268. The co-crystal structure of the DCAF1-OICR-41103 complex reveals the ligand's binding mode within the WDR central pocket, demonstrating its potential for PROTAC design and development. Notably, OICR-41103 effectively displaces the lentiviral Vpr protein from DCAF1 in both biochemical and cellular settings, highlighting its potential for the development of HIV therapeutics.

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