Search

Graphical abstract Abstract The protein-protein interaction between WDR5 (WD40 repeat protein 5) and MLL1 (mixed-lineage leukemia 1) is important for maintaining optimal H3K4 methyltransferase activity of MLL1. Dysregulation of MLL1 catalytic function is relevant to mixed-lineage leukemia, and targeting WDR5-MLL1 interaction could be a promising therapeutic strategy for leukemia harboring MLL1 fusion proteins. To date, several peptidomimetic and non-peptidomimetic small-molecule inhibitors targeting WDR5-MLL1 interaction have been reported, yet the discovery walk of new drugs inhibiting MLL1 methytransferase activity is still in its infancy. It's urgent to find other small-molecule WDR5-MLL1 inhibitors with novel scaffolds. In this study, through fluorescence polarization (FP)-based high throughput screening, several small-molecule inhibitors with potent inhibitory activities in vitro against WDR5-MLL1 interaction were discovered. Nuclear Magnetic Resonance (NMR) assays were carried out to confirm the direct binding between hit compounds and WDR5. Subsequent similarity-based analog searching of the 4 hits led to several inhibitors with better activity, among them, DC_M5_2 displayed highest inhibitory activity with IC 50 values of 9.63 ± 1.46 µM. Furthermore, a molecular docking study was performed and disclosed the binding modes and interaction mechanisms between two most potent inhibitors and WDR5. [ABSTRACT FROM AUTHOR]

Abstract Although mutated Ras protein is well recognized as an important drug target, direct targeting Ras has proven to be a daunting task. Recent studies demonstrated that Ras protein needs PDEδ to relocate to plasma membrane to execute its signaling transduction function, which provides a new avenue for modulating the Ras protein. To find small molecules antagonizing the interactions between PDEδ and Ras, here we presented a successful application of fragment-based drug discovery of PDEδ inhibitors. Under the guidance of crystal structures, we are able to quickly optimize the initial fragment into highly potent inhibitors, with more than 2000-fold improvement in binding activity, which further adds to the arsenal towards the inhibition of Ras signaling in cancer therapy. Graphical abstract Image 1 Highlights • Fragment-based approach was used to discover a new chemotype targeting PDEδ-Ras interaction. • Scaffold modification was undertaken on the basis of co-crystal structure and resulted in an optimizable hit. • Two rounds of optimization quickly improved the binding activity by more than 1000 fold. • Biological study indicates the PDEδ-Ras inhibitor could affect the downstream Ras signaling. [ABSTRACT FROM AUTHOR]

PolycombRepressive Complex 2 (PRC2) modulates the chromatin structureand transcriptional repression by trimethylation lysine 27 of histoneH3 (H3K27me3), a process that necessitates the protein–proteininteraction (PPI) between the catalytic subunit EZH2 and EED. DeregulatedPRC2 is intimately involved in tumorigenesis and progression, makingit an invaluable target for epigenetic cancer therapy. However, untilnow, there have been no reported small molecule compounds targetingthe EZH2-EED interactions. In the present study, we identified astemizole,an FDA-approved drug, as a small molecule inhibitor of the EZH2-EEDinteraction of PRC2. The disruption of the EZH2-EED interaction byastemizole destabilizes the PRC2 complex and inhibits its methyltransferaseactivity in cancer cells. Multiple lines of evidence have demonstratedthat astemizole arrests the proliferation of PRC2-driven lymphomasprimarily by disabling the PRC2 complex. Our findings demonstratethe chemical tractability of the difficult PPI target by a small moleculecompound, highlighting the therapeutic promise for PRC2-driven humancancers via targeted destruction of the EZH2-EED complex. [ABSTRACT FROM AUTHOR]