Discovery of Nanomolar DCAF1 Small Molecule Ligands

Abstract

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4 DCAF1 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-billioncompound 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 K D of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR K D of 38 nM and cellular target engagement with EC 50 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.

Discovery of a Novel DCAF1 Ligand Using a Drug–Target Interaction Prediction Model: Generalizing Machine Learning to New Drug Targets

“…Since the deposition of the DCAF1-CYCA-117-70 structure (PDB 7SSE), the first publicly released cocrystal structure of DCAF1 bound to a small molecule, there have been notable advances in the discovery of small molecules for DCAF1, ,, further validating that DCAF1 is not only a novel target but also a highly tractable and promising E3 ligase. Indeed, while this manuscript was under revision, two series of DCAF1 ligands were reported. , One series is derived from a ligand discovered via DNA-encoded chemical library screening that binds deeper in the WDR central cavity and therefore does not overlap with viral accessory proteins Vpr/x binding to the DCAF1 WDR domain (Figure S3A). A compound from the second series subsequently turned into a DCAF1-recruiting PROTAC is less deeply bound in the central WDR cavity, in a binding pose that is very similar to CYCA-117-70 (Figure S3B).…”

Discovery of New Binders for DCAF1, an Emerging Ligase Target in the Targeted Protein Degradation Field

“…At the time of the writing of this manuscript, a novel series of small molecule ligands targeting DCAF1 has been reported . The ligands of this new chemical class bind in the donut pocket but occupy a different region with respect to the binders reported here (Figure a,b) with only a minor overlap (Figure S8).…”

“…DCAF1 crystal structures in complex with (a) compound 8 (PDB ID: 8OGB) and (b) compound 26e of reference (PDB ID: 8F8E). (c) DCAF1 crystal structure deposited in PDB under the code 7SSE.…”

Pharmacophore-based ML model to predict ligand selectivity for E3 ligase binders

“…This yielded a total of 643 unique ligands. Additionally, we expanded the chemical space of E3 binders with 19 ligands specific to DDB1 and CUL4 associated factor 1 (DCAF1) which were not present in PROTACsderived collections (Li et al, 2023). The summary of the dataset of unique 662 compounds alongside the seventeen E3 ligases targets is shown in Figure 1.…”