Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression
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Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.
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The latter study's series of very potent degraders yield high FFC values when explored through the computational approach.
“That said, the latter study reports a series of very potent degraders 62, and indeed these yield high FFC values when explored through our computational approach (Table S1).”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [62]
QCA570 is the most potent BET PROTAC, displaying picomolar potency against human acute leukemia cell lines in vitro and in vivo.
“QCA570 is the most potent BET PROTAC that displays picomolar potency against human acute leukemia cell lines in vitro and in vivo [93].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [93]
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Self-citationPROTAC therapy as a new targeted therapy for lung cancer
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Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders
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- Authors
- Qin, C., Hu, Y., Zhou, B., Fernandez-Salas, E., Yang, C.-Y., Liu, L., McEachern, D., Przybranowski, S., Wang, M., Stuckey, J., Meagher, J., Bai, L., Chen, Z., Lin, M., Yang, J., Ziazadeh, D. N., Xu, F., Hu, J., Xiang, W., Huang, L., Li, S., Wen, B., Sun, D., & Wang, S.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-07-18
- Volume
- 61
- Issue
- 15
- Pages
- 6685-6704
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC6545111
- OpenAlex
- W2883182240
- Cited by
- 281
- References
- 57
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 37 · 2023: 30 · 2022: 40 · 2021: 40 · 2020: 48 · 2019: 42 · 2018: 3
- FWCI
- 12.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Funders
- National Cancer Institute (R01 CA215758, P30 CA046592)
- Breast Cancer Research Foundation
- Prostate Cancer Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and pharmacology of benzodiazepine derivatives
- Keywords
- PROTAC degraders, BET proteins, structure-based drug design, acute leukemia, tumor regression, xenograft models, epigenetic reader protein, small-molecule degraders
- MeSH terms
- Bromodomain Containing Proteins, Animals, Dose-Response Relationship, Drug, Female, Humans, Models, Molecular, Protein Conformation, Proteins, Drug Design, Cell Line, Tumor, Mice, Small Molecule Libraries, Proteolysis
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