Discovery of CZL-046 with an (<i>S</i>)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma
E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an (<i>S</i>)-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound <b>29</b> (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC<sub>50</sub> = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC<sub>50</sub> = 51.5 nM). <b>29</b> suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound <b>5</b>, <b>29</b> exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of <b>29</b> with 30 mg/kg achieved a TGI value of 44% in the OPM-2 xenograft model, accompanied by good tolerability. The cocrystal structure of CREB binding protein bromodomain with <b>29</b> provides an insight into the precise binding mode. The results demonstrate that <b>29</b> is a promising p300 bromodomain inhibitor for the treatment of MM.
Authors
- Qiongyu Shi
- Cheng Zhang (ORCID: https://orcid.org/0000-0002-5185-9240)
- Xiaodong Lyu (ORCID: https://orcid.org/0000-0002-0155-5927)
- Yingxia Li (ORCID: https://orcid.org/0000-0001-6782-8740)
- Yuting Huang (ORCID: https://orcid.org/0000-0001-9986-5124)
- Zonglong Chen (ORCID: https://orcid.org/0000-0003-4733-8255)
- Yue Deng (ORCID: https://orcid.org/0000-0001-8963-3928)
- Xun Huang (ORCID: https://orcid.org/0000-0002-2653-8293)
- Ying Zhang (ORCID: https://orcid.org/0000-0003-2194-7116)
- Yan Zhang (ORCID: https://orcid.org/0000-0002-5307-2484)
- Zekun Wang (ORCID: https://orcid.org/0000-0002-4760-3074)
- Hong Yang (ORCID: https://orcid.org/0000-0002-8806-1240)
- Xingcan Wang
- Yong Xu (ORCID: https://orcid.org/0000-0003-3601-0246)
- Yujie Wang (ORCID: https://orcid.org/0009-0009-2732-1991)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Materia Medica (CN)
- State Key Laboratory of Respiratory Disease (CN)
- Huashan Hospital (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01984
- Citations
- 9
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- National Natural Science Foundation of China
- Qingdao National Laboratory for Marine Science and Technology
- Program of Shanghai Subject Chief Scientist
- National Key Research and Development Program of China