Cyclica and the Structural Genomics Consortium Co-crystallize DCAF1, a Key Component in Proteasomal Degradation, With a Novel Ligand to Support Targeted Therapeutics Discovery

As part of the initiative, the SGC and Cyclica examined three WDR proteins to discover small molecule binders using Cyclica’s proprietary deep learning platform to assess commercially available libraries for potential binders. Upon biophysical analysis performed by the SGC, Cyclica successfully identified hit molecules for DCAF1 which were further verified in several subsequent experiments. The SGC proceeded to co-crystallize Cyclica’s hit molecule with DCAF1 protein, which has been submitted to the Protein Data Bank (PDB) as the first disclosed co-crystal structure of DCAF1 with a small molecule bound (PDB code: 7SSE) Dr. Vijay Shahani, Cyclica’s Director of Applied Science, shares his enthusiasm for the project by indicating “At Cyclica, we believe in advancing our own internal drug discovery pipeline while also contributing to open science for the betterment of future opportunities. Our work with the SGC to discover probes to better understand DCAF1 biology has led to the fantastic result of a co-crystallized structure that we’ll be making publicly available. With this critical finding, we will continue to drive the development of these compounds, whilst simultaneously evaluating the therapeutic potential for binders of DCAF1. It’s been a pleasure working with the world class team at the SGC, and we eagerly await the next opportunity to have more impact together.”

The newly determined DCAF1 co-crystal structure can now be used to discover new molecules to probe the biology of DCAF1, a protein involved in ubiquitination and proteasome-dependent degradation of proteins linked to human disease. DCAF1 ligands may prove a useful component in PROTAC molecules targeting proteins for degradation. PROTACs and molecular glues represent a promising therapeutic modality to target proteins not amenable to traditional drugs that directly impact protein function. Harnessing DCAF1 could expand the applicable target space for PROTACs expanding future therapeutic applications.

Dr. Cheryl Arrowsmith, Chief Scientist for the SGC Toronto laboratory, comments on the innovative collaboration and how these impactful findings were uncovered, “together we readily discovered a starting point (hit) for chemical probe development to an ‘unprecedented’ target (DCAF1). This was achieved by testing approximately 100 compounds predicted by Cyclica’s deep learning platform, compared to ‘traditional’ methods, which would have required testing thousands of molecules experimentally. Working with Cyclica has reinforced our belief in computational hit discovery, which will play a key role in the Target2035 initiative.”

Cyclica is one of three artificial intelligence companies with which the SGC selected to collaborate on this initiative.

About Cyclica

Cyclica is the partner of choice for data-driven drug discovery. We advance molecules that embrace the complexity of disease. Our work spans dozens of collaborations with large pharma and biotech as well as several joint ventures. We are a passionate team of biotech and pharma professionals, biologists, chemists, and computer scientists who live and labour at the intersection of our collective expertise. To learn more about Cyclica and how we partner, please visit www.cyclicarx.com

About the SGC

The Structural Genomics Consortium is a global public-private partnership dedicated to open science and that seeks to accelerate drug discovery by fostering collaboration among a large network of scientists in academia and industry and by making all research outputs openly available to the scientific community. The current SGC research hubs are in Canada, Germany, Sweden, the United Kingdom, and the United States.

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