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

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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Journal
Communications Biology
Published
2025-07-19
DOI
https://doi.org/10.1038/s42003-025-08491-0
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Taira Kiyota, Paul Gehrtz, Brigitte L. Thériault, Serah Kimani et al.
Communications Biology
Protein Degradation and Inhibitors
article

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

Taira Kiyota, Paul Gehrtz, Brigitte L. Thériault, Serah Kimani, P. Loppnau, C.H. Arrowsmith, Levon Halabelian, Sarah J. Tucker, Punit Saraon, Dalia Baršytė-Lovejoy, Magdalena M. Szewczyk, Rima Al‐awar, David Uehling, Manuel Chan, Ahmed Mamai, Taraneh Hajian, Almagul Seitova, Ji Sup Kim, Gennady Poda, Vijayaratnam Santhakumar, Ahmed M. Aman, Mahmoud Noureldin, Alice Shi Ming Li, Richard Marcellus, Stuart R. Green, Dhananjay Joshi, Héctor González-Álvarez, Peter J. Brown, Anand Vala, Suzanne Ackloo, Yanjun Li, Mohammed Mohammed, A. Dong, Laurent Hoffer, Chiara Krausser, Jailall Ramnauth, Bhimsen Rout, Brian J. Wilson, Bhashant Patel, Vaibhavi Rathod, Tobias Hammann, Paras Jagodra
article en

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.

Communications BiologyVol. 8(1)
Ontario Institute for Cancer Research (CA), University of North Carolina at Chapel Hill (US), University Health Network (CA), Merck KGaA, Darmstadt (Germany) (DE), University of Toronto (CA), Princess Margaret Cancer Centre (CA), Structural Genomics Consortium (CA), Piramal (India) (IN)
Bristol-Myers Squibb, Pfizer, Bayer, Canadian Light Source, McGill University, Genome Canada, Merck KGaA, Ontario Genomics, European Federation of Pharmaceutical Industries and Associations, Government of Ontario, Ontario Genomics Institute, Genentech, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada
Good health and well-being
Openalex Percentile: Top 84%
Protein Degradation and Inhibitors
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