BIX-01294 inhibits oncoproteins NSD1, NSD2 and NSD3
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NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 make up the nuclear receptor-binding Su(var)3-9, Enhancer-of-zeste and Trithorax domain family of histone methyltransferases, which are essential for regulating the chromatin. Abnormalities in histone methyltransferases function are increasingly being found to be associated with numerous pathological conditions, including carcinogenesis and tumor progression. NSD1, NSD2, and NSD3 are oncoproteins aberrantly expressed in numerous cancers in which selective inhibition may offer therapeutic opportunities, especially in cases of conditions with poor prognoses such as multiple myeloma. Histone methyltransferase inhibitors are scarce and selective inhibitors are being explored. NSD inhibitors are urgently needed. BIX-01294 is a G9a-like protein/G9a histone methyltransferase inhibitor commonly used to modulate H3K9 methylation in the context of cell reprogramming and cancer biology with in vitro IC50 values of 0.7 and 1.9 μM, respectively. Since the catalytic Su(var)3-9, Enhancer-of-zeste and Trithorax domain of the NSDs is highly related to that of G9a-like protein and G9a, we investigated the potentially differential NSDs inhibition by BIX-01294. In this study, we identified BIX-01294 as an NSD in vitro hit compound that differentially inhibits H3K36 methylation by NSD1, NSD2, and NSD3 with IC50 values of 40 ~ 112 μM. Furthermore, we investigated the molecular basis of inhibition by BIX-01294 on the NSDs and discuss the prospects of BIX-01294 derivatives for selective NSD inhibition.
KeywordsBIX-01294, Inhibitor NSD1 NSD2/MMSET/WHSC1 NSD3/WHSC1L1
Su(var)3-9, Enhancer-of-zeste and Trithorax
Nuclear receptor-binding SET domain
Histone lysine methyltransferase
Ms. Yeonjeong Roh is acknowledged for her technical support in processing the MALDI-TOF mass spectrometry data and for her assistance for the Fig. 1c.
This study is supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology to EDL (2015K2A1B8064967) and MM (2016R1D1A1B01014286). The School of Life Sciences, BK21 Plus KNU Creative BioResearch Group at Kyungpook National University is acknowledged for its support.
EDL and MM conceived and designed the experiments; MM, DM, YS, and SZ performed the experiments; EDL, MM, DM and SZ analyzed the data; and DM, YS, MM, and EDL drafted the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
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