Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins
Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded library (DEL) screening is a core platform technology increasingly used to identify drugs that bind to protein targets. Here, we use DEL screening against bromodomain and extra-term...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123001099 |
| _version_ | 1797831790768947200 |
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| author | Seoyeon Jeong Hwa-Ryeon Kim June-Ha Shin Min-Hee Son In-Hyun Lee Jae-Seok Roe |
| author_facet | Seoyeon Jeong Hwa-Ryeon Kim June-Ha Shin Min-Hee Son In-Hyun Lee Jae-Seok Roe |
| author_sort | Seoyeon Jeong |
| collection | DOAJ |
| description | Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded library (DEL) screening is a core platform technology increasingly used to identify drugs that bind to protein targets. Here, we use DEL screening against bromodomain and extra-terminal motif (BET) proteins to identify inhibitors with new chemotypes, and successfully identified BBC1115 as a selective BET inhibitor. While BBC1115 does not structurally resemble OTX-015, a clinically active pan-BET inhibitor, our intensive biological characterization revealed that BBC1115 binds to BET proteins, including BRD4, and suppresses aberrant cell fate programs. Phenotypically, BBC1115-mediated BET inhibition impaired proliferation in acute myeloid leukemia, pancreatic, colorectal, and ovarian cancer cells in vitro. Moreover, intravenous administration of BBC1115 inhibited subcutaneous tumor xenograft growth with minimal toxicity and favorable pharmacokinetic properties in vivo. Since epigenetic regulations are ubiquitously distributed across normal and malignant cells, it will be critical to evaluate if BBC1115 affects normal cell function. Nonetheless, our study shows integrating DEL-based small-molecule compound screening and multi-step biological validation represents a reliable strategy to discover new chemotypes with selectivity, efficacy, and safety profiles for targeting proteins involved in epigenetic regulation in human malignancies. |
| first_indexed | 2024-04-09T13:57:21Z |
| format | Article |
| id | doaj.art-fc2d400b546f4c0c8eba57b2ad04436d |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-09T13:57:21Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-fc2d400b546f4c0c8eba57b2ad04436d2023-05-08T04:09:17ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-06-0132637649Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteinsSeoyeon Jeong0Hwa-Ryeon Kim1June-Ha Shin2Min-Hee Son3In-Hyun Lee4Jae-Seok Roe5Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, KoreaDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, KoreaDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, KoreaBenobio Co., Ltd., Seoul, KoreaBenobio Co., Ltd., Seoul, KoreaDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea; Corresponding author: Jae-Seok Roe, PhD, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded library (DEL) screening is a core platform technology increasingly used to identify drugs that bind to protein targets. Here, we use DEL screening against bromodomain and extra-terminal motif (BET) proteins to identify inhibitors with new chemotypes, and successfully identified BBC1115 as a selective BET inhibitor. While BBC1115 does not structurally resemble OTX-015, a clinically active pan-BET inhibitor, our intensive biological characterization revealed that BBC1115 binds to BET proteins, including BRD4, and suppresses aberrant cell fate programs. Phenotypically, BBC1115-mediated BET inhibition impaired proliferation in acute myeloid leukemia, pancreatic, colorectal, and ovarian cancer cells in vitro. Moreover, intravenous administration of BBC1115 inhibited subcutaneous tumor xenograft growth with minimal toxicity and favorable pharmacokinetic properties in vivo. Since epigenetic regulations are ubiquitously distributed across normal and malignant cells, it will be critical to evaluate if BBC1115 affects normal cell function. Nonetheless, our study shows integrating DEL-based small-molecule compound screening and multi-step biological validation represents a reliable strategy to discover new chemotypes with selectivity, efficacy, and safety profiles for targeting proteins involved in epigenetic regulation in human malignancies.http://www.sciencedirect.com/science/article/pii/S2162253123001099MT: BioinformaticsDNA-encoded libraryBET proteinshistone acetylationMYCepigenetic therapy |
| spellingShingle | Seoyeon Jeong Hwa-Ryeon Kim June-Ha Shin Min-Hee Son In-Hyun Lee Jae-Seok Roe Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins Molecular Therapy: Nucleic Acids MT: Bioinformatics DNA-encoded library BET proteins histone acetylation MYC epigenetic therapy |
| title | Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins |
| title_full | Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins |
| title_fullStr | Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins |
| title_full_unstemmed | Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins |
| title_short | Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins |
| title_sort | streamlined dna encoded small molecule library screening and validation for the discovery of novel chemotypes targeting bet proteins |
| topic | MT: Bioinformatics DNA-encoded library BET proteins histone acetylation MYC epigenetic therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123001099 |
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