2. Academic Validation
  3. Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma

Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma

  • J Med Chem. 2024 Oct 24;67(20):18606-18628. doi: 10.1021/acs.jmedchem.4c01984.
Zonglong Chen 1,  Hong Yang 2,  Yan Zhang 3,  Xiaodong Lyu 1,  Qiongyu Shi 2,  Cheng Zhang 3,  Xingcan Wang 4,  Zekun Wang 4,  Ying Zhang 2 5,  Yue Deng 4,  Yujie Wang 1,  Yuting Huang 2 6,  Yong Xu 3,  Xun Huang 2 5 6 7,  Yingxia Li 1 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 2 Lingang Laboratory, Shanghai 200031, P. R. China.
  • 3 China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 4 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 5 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 6 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 7 School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P. R. China.
  • 8 Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
PMID: 39356741 DOI: 10.1021/acs.jmedchem.4c01984
Abstract

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 (S)-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound 29 (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC50 = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC50 = 51.5 nM). 29 suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound 5, 29 exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of 29 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 29 provides an insight into the precise binding mode. The results demonstrate that 29 is a promising p300 bromodomain inhibitor for the treatment of MM.

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