Response to Scripps Research Institute Paper on DCAF-1

A vast majority of protein targets in the human proteome have been deemed undruggable given the conventional technologies available to tackle them. Cyclica has spent the past 10 years building methods to explore the entire human proteome with the goal to drug the undrugged protein targets that are viewed as recalcitrant to existing technologies. In 2021, Cyclica joined forces with the Structural Genomics Consortium (SGC) as part of its Target 2035 initiative to use Cyclica’s proprietary MatchMaker technology to identify the first small molecule to bind a low-data protein target, DCAF1. Independent from our work, researchers at the Scripps Institute were also working on DCAF1, and the results are really interesting. But first, let’s talk about DCAF1.

DCAF1 was originally  identified as a putative antiviral host target and more broadly as a promising target to facilitate proteasome-mediated degradation of therapeutic targets as a part of a E3 ubiquitin ligase complex. It has a complex domain architecture that includes a WD40 repeat (WDR) domain, which is one of the most abundant protein-protein interactions (PPIs) domains in the human proteome. Given the significant role that PPIs play in many cellular processes and diseases, there has been renewed interest in exploring WDR domain proteins, including DCAF1.

As part of the initiative, Cyclica’s drug discovery team used its proprietary deep learning, proteome wide platform to identify novel pockets and discover small molecule 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. In November 2021, this co-crystal structure was submitted to the Protein Data Bank (PDB) as the first disclosed co-crystal structure of DCAF1 with a small molecule bound (PDB code: 7SSE). The decision to make this discovery available was a result of both Cyclica’s and the SGC’s commitment to open science. We strongly believe that we have a moral obligation to continue to advance science in a way that others can build off or extend. 

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. It is believed that DCAF1 ligands may prove a useful component in PROTAC molecules targeting proteins for degradation, and that harnessing DCAF1 could expand the applicable target space for PROTACs expanding future therapeutic applications. 

Fast forward almost a year, and Tao et al from The Scripps Research Institute published  a paper on Sept 29, 2022 (here) based on their own work on DCAF1. What’s most exciting about this paper (beyond the acknowledgement of Cyclica’s reversible molecule CYCA-117-70) is that the researchers at The Scripps confirmed DCAF1 as a validated PROTAC E3-ligase. As noted in the paper, this is an important finding as “to date, small-molecule ligands have been discovered for only a limited number of E3 ligases, which is an important limiting factor for realizing the full potential of targeted protein degradation.” What’s also really exciting about this is that the researchers relied on physics-based computational modeling to dock their ligands to figure out the pocket, and Cyclica’s co-crystal structure was included as it supported their models that this was a druggable pocket. 

This is a great paper, focusing on a target that Cyclica has collaborated on with SGC, and kudos needs to be paid to the team at Scripps for their diligent work to develop this PROTAC.

Have a look at the project details on the initiative with the SGC, led by Julie Owen, Drug Discovery team lead, here.

Naheed Kurji, Chief Executive Officer

Naheed Kurji, Chief Executive Officer

Naheed Kurji is the Co-Founder, President and CEO of Cyclica. Naheed is passionate about building AI-augmented technologies that enable researchers to make more strategic and informed decisions in Healthcare and the life sciences. He spends the majority of his time obsessing over Cyclica’s culture, defining its strategy to best effect change in the pharma industry to achieve the company’s vision, and exploring opportunities for continued innovation.

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