Theranostics 2021; 11(17):8172-8184. doi:10.7150/thno.56737 This issue Cite

Research Paper

Small-molecule inhibitor of AF9/ENL-DOT1L/AF4/AFF4 interactions suppresses malignant gene expression and tumor growth

Fangrui Wu1,2,*, Shenyou Nie1,*, Yuan Yao1,*, Tong Huo1,*, Xin Li1, Xiaowei Wu1, Jidong Zhao1, Yi-Lun Lin1, Yinjie Zhang1, Qianxing Mo3, Yongcheng Song1,2,✉

1. Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
2. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
3. H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA.
* These authors contributed equally.

Citation:
Wu F, Nie S, Yao Y, Huo T, Li X, Wu X, Zhao J, Lin YL, Zhang Y, Mo Q, Song Y. Small-molecule inhibitor of AF9/ENL-DOT1L/AF4/AFF4 interactions suppresses malignant gene expression and tumor growth. Theranostics 2021; 11(17):8172-8184. doi:10.7150/thno.56737. https://www.thno.org/v11p8172.htm
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Abstract

Graphic abstract

Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis. MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%). The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L. Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia. Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target.

Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological activities against MLL-rearranged leukemia and other cancer cells.

Results: Compound-1 was identified to be a novel small-molecule inhibitor of the AF9/ENL-DOT1L/AF4/AFF4 interaction with IC50s of 0.9-3.5 µM. Pharmacological inhibition of the PPIs significantly reduced SEC and DOT1L-mediated H3K79 methylation in the leukemia cells. Gene profiling shows compound-1 significantly suppressed the gene signatures related to onco-MLL, DOT1L, HoxA9 and Myc. It selectively inhibited proliferation of onco-MLL- or Myc-driven cancer cells and induced cell differentiation and apoptosis. Compound-1 exhibited strong antitumor activity in a mouse model of MLL-rearranged leukemia.

Conclusions: The AF9/ENL-DOT1L/AF4/AFF4 interactions are validated to be an anticancer target and compound-1 is a useful in vivo probe for biological studies as well as a pharmacological lead for further drug development.

Keywords: MLL-rearranged leukemia, Super elongation complexes, Protein-protein interaction, Small-molecule inhibitor, Cancer therapeutics


Citation styles

APA
Wu, F., Nie, S., Yao, Y., Huo, T., Li, X., Wu, X., Zhao, J., Lin, Y.L., Zhang, Y., Mo, Q., Song, Y. (2021). Small-molecule inhibitor of AF9/ENL-DOT1L/AF4/AFF4 interactions suppresses malignant gene expression and tumor growth. Theranostics, 11(17), 8172-8184. https://doi.org/10.7150/thno.56737.

ACS
Wu, F.; Nie, S.; Yao, Y.; Huo, T.; Li, X.; Wu, X.; Zhao, J.; Lin, Y.L.; Zhang, Y.; Mo, Q.; Song, Y. Small-molecule inhibitor of AF9/ENL-DOT1L/AF4/AFF4 interactions suppresses malignant gene expression and tumor growth. Theranostics 2021, 11 (17), 8172-8184. DOI: 10.7150/thno.56737.

NLM
Wu F, Nie S, Yao Y, Huo T, Li X, Wu X, Zhao J, Lin YL, Zhang Y, Mo Q, Song Y. Small-molecule inhibitor of AF9/ENL-DOT1L/AF4/AFF4 interactions suppresses malignant gene expression and tumor growth. Theranostics 2021; 11(17):8172-8184. doi:10.7150/thno.56737. https://www.thno.org/v11p8172.htm

CSE
Wu F, Nie S, Yao Y, Huo T, Li X, Wu X, Zhao J, Lin YL, Zhang Y, Mo Q, Song Y. 2021. Small-molecule inhibitor of AF9/ENL-DOT1L/AF4/AFF4 interactions suppresses malignant gene expression and tumor growth. Theranostics. 11(17):8172-8184.

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