Discovery of Nanomolar DCAF1 Small Molecule Ligands

  • J Med Chem. 2023 Apr 13;66(7):5041-5060. doi: 10.1021/acs.jmedchem.2c02132.
Alice Shi Ming Li  1  2  3 Serah Kimani  1  4 Brian Wilson  2 Mahmoud Noureldin  2  3 Héctor González-Álvarez  2  3 Ahmed Mamai  2 Laurent Hoffer  2 John P Guilinger  5 Ying Zhang  5 Moritz von Rechenberg  6 Jeremy S Disch  6 Christopher J Mulhern  6 Belinda L Slakman  6 John W Cuozzo  6 Aiping Dong  1 Gennady Poda  2  7 Mohammed Mohammed  2 Punit Saraon  2 Manish Mittal  8 Pratik Modh  8 Vaibhavi Rathod  8 Bhashant Patel  8 Suzanne Ackloo  1 Vijayaratnam Santhakumar  1 Magdalena M Szewczyk  1 Dalia Barsyte-Lovejoy  1  3 Cheryl H Arrowsmith  1  4  9 Richard Marcellus  2 Marie-Aude Guié  5 Anthony D Keefe  5 Peter J Brown  1 Levon Halabelian  1  3 Rima Al-Awar  2  3  10 Masoud Vedadi  1  2  3
Affiliations
  • 1. Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 2. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
  • 3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 4. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada.
  • 5. X-Chem Inc., Waltham, Massachusetts 02453, United States.
  • 6. Relay Therapeutics, Cambridge, Massachusetts 02139, United States.
  • 7. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
  • 8. Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Ahmedabad, Gujarat 382213, India.
  • 9. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 10. Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.
Abstract

DCAF1 is a substrate receptor of two distinct E3 Ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 μM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward Cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

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