Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rea...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/21/5283 |
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| author | Xin Li Xiaowei Wu Shenyou Nie Jidong Zhao Yuan Yao Fangrui Wu Chandra Bhushan Mishra Md Ashraf-Uz-Zaman Bala Krishna Moku Yongcheng Song |
| author_facet | Xin Li Xiaowei Wu Shenyou Nie Jidong Zhao Yuan Yao Fangrui Wu Chandra Bhushan Mishra Md Ashraf-Uz-Zaman Bala Krishna Moku Yongcheng Song |
| author_sort | Xin Li |
| collection | DOAJ |
| description | Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC<sub>50</sub> values as low as 1.6 μM. Structure–activity relationship studies of 77 benzothiophene and related indole and benzofuran compounds show that a 4-piperidin-1-ylphenyl or 4-pyrrolidin-1-ylphenyl substituent is essential for the activity. The inhibitors suppressed expression of MLL target genes HoxA9, Meis1 and Myc, and selectively inhibited proliferation of MLL-r and other acute myeloid leukemia cells with EC<sub>50</sub> values as low as 4.7 μM. These inhibitors are useful chemical probes for biological studies of AF9/ENL, as well as pharmacological leads for further drug development against MLL-r and other leukemias. |
| first_indexed | 2024-03-11T11:33:09Z |
| format | Article |
| id | doaj.art-ee206a286c234efb90dc22cdd5165fb4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T11:33:09Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ee206a286c234efb90dc22cdd5165fb42023-11-10T15:00:30ZengMDPI AGCancers2072-66942023-11-011521528310.3390/cancers15215283Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1LXin Li0Xiaowei Wu1Shenyou Nie2Jidong Zhao3Yuan Yao4Fangrui Wu5Chandra Bhushan Mishra6Md Ashraf-Uz-Zaman7Bala Krishna Moku8Yongcheng Song9Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAVerna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USAChromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC<sub>50</sub> values as low as 1.6 μM. Structure–activity relationship studies of 77 benzothiophene and related indole and benzofuran compounds show that a 4-piperidin-1-ylphenyl or 4-pyrrolidin-1-ylphenyl substituent is essential for the activity. The inhibitors suppressed expression of MLL target genes HoxA9, Meis1 and Myc, and selectively inhibited proliferation of MLL-r and other acute myeloid leukemia cells with EC<sub>50</sub> values as low as 4.7 μM. These inhibitors are useful chemical probes for biological studies of AF9/ENL, as well as pharmacological leads for further drug development against MLL-r and other leukemias.https://www.mdpi.com/2072-6694/15/21/5283MLL-rearranged leukemiasuper elongation complexessmall-molecule inhibitorprotein–protein interactioncancer therapeutics |
| spellingShingle | Xin Li Xiaowei Wu Shenyou Nie Jidong Zhao Yuan Yao Fangrui Wu Chandra Bhushan Mishra Md Ashraf-Uz-Zaman Bala Krishna Moku Yongcheng Song Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L Cancers MLL-rearranged leukemia super elongation complexes small-molecule inhibitor protein–protein interaction cancer therapeutics |
| title | Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L |
| title_full | Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L |
| title_fullStr | Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L |
| title_full_unstemmed | Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L |
| title_short | Discovery, Structure–Activity Relationship and In Vitro Anticancer Activity of Small-Molecule Inhibitors of the Protein–Protein Interactions between AF9/ENL and AF4 or DOT1L |
| title_sort | discovery structure activity relationship and in vitro anticancer activity of small molecule inhibitors of the protein protein interactions between af9 enl and af4 or dot1l |
| topic | MLL-rearranged leukemia super elongation complexes small-molecule inhibitor protein–protein interaction cancer therapeutics |
| url | https://www.mdpi.com/2072-6694/15/21/5283 |
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