Purpose(s)
The treatment of tumors driven by overexpression or amplification of MYC oncogenes remains a significant challenge in drug discovery. WD repeat-containing protein 5 (WDR5) is a crucial partner in the facilitated recruitment of MYC to chromatin, thus making it a critical cofactor for MYC-driven tumorigenesis. Inhibitors of WDR5 are being sought as highly attractive options for the treatment of multiple cancer types.
Method(s)
In this work, utilizing a high-throughput screening campaign, we identify small molecule inhibitors of WDR5-MYC protein-protein interaction with potent in vitro binding affinity.
Result(s)
Table 1. Inhibition of compounds at a concentration of 50 µM
Figure 1. Affinity of compounds to WDR5
Table 2. Cell proliferation inhibition of compounds
Conclusion(s)
The discovery of WDR5 as a critical cofactor required for the recruitment of MYC to a subset of genomic targets encouraged us to search for small molecules inhibitors of the WDR5-MYC interaction. We sought to identify small molecule inhibitors with drug-like properties that would enable further studies to examine validation of this approach to treat MYC-driven cancers.
Using high-throughput screening campaign, we found multiple compounds showed excellent inhibition ability, and the inhibition rate was higher than SADS-1（Macdonald JD et al, J Med Chem. 62(24):11232-11259(2019) at the same concentration. CBHM 13 was bestin-class of series, exhibiting high binding affinity (Kd = 3.4 μM) in the FP and inhibited the proliferation of tumor cells (IC50 = 20.0 μM/16.9 μM), while SADS-1 could not effectively inhibit the growth of tumor cells.