Histone methyltransferases are involved in many important biological processes, and abnormalities in these enzymes are associated with tumorigenesis and progression. Disruptor of telomeric silencing 1-like (DOT1L), a key hub in histone lysine methyltransferases, has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias and validated to be a potential therapeutic target. In this study, we identified a novel DOT1L inhibitor, DC_L115 (CAS no. 1163729-79-0), by combining structure-based virtual screening with biochemical analyses. This potent inhibitor DC_L115 shows high inhibitory activity toward DOT1L (IC50 = 1.5 μM). Through a process of surface plasmon resonance-based binding assays, DC_L115 was founded to bind to DOT1L with a binding affinity of 0.6 μM in vitro. Moreover, this compound selectively inhibits MLL-rearranged cell proliferation with an IC50 value of 37.1 μM. We further predicted the binding modes of DC_L115 through molecular docking analysis and found that the inhibitor competitively occupies the binding site of S-adenosylmethionine. Overall, this study demonstrates the development of potent DOT1L inhibitors with novel scaffolds.

Polycomb repressive complex 2 (PRC2) acts as a primary writer for di- and tri-methylation of histone H3 at lysine 27. This protein plays an essential role in silencing gene expression. Enhancer of zeste 2 (EZH2), the catalytic subunit of PRC2, is considered as a promising therapeutic target for cancer. GSK126, a specific inhibitor of EZH2, is undergoing phase I trials for hypermethylation-related cancers. In addition, many derivatives of GSK126 are also commonly used in laboratory investigations. However, studies on the mechanism and drug development of EZH2 are limited by the absence of structural diversity of these inhibitors because they share similar SAM-like scaffolds. In this study, we generated a pharmacophore model based on reported EZH2 inhibitors and performed in silico screenings. Experimental validations led to the identification of two novel EZH2 inhibitors, DCE_42 and DCE_254, with IC50 values of 23 and 11 μM, respectively. They also displayed significant anti-proliferation activity against lymphoma cell lines. Thus, we discovered potent EZH2 inhibitors with novel scaffold using combined in silico screening and experimental study. Results from this study can also guide further development of novel specific EZH2 inhibitors.

A series of new docetaxol analogues have been designed and synthesized. And their cytotoxicities against cancer cells have been evaluated by MTT method. Most of these compounds showed selective inhibitions on human cancer cell lines. Among them, compound 8 exhibited higher inhibitory activity than Paclitaxel (Taxol) against several cancer cell lines. This work indicated that appropriate modification at C-7 and C-10 of docetaxel might be a promising approach for this unique class of anticancer compounds.