2. Academic Validation
  3. Optimization and Biological Evaluation of Novel 1 H-Pyrrolo[2,3- c]pyridin Derivatives as Potent and Reversible Lysine Specific Demethylase 1 Inhibitors for the Treatment of Acute Myelogenous Leukemia

Optimization and Biological Evaluation of Novel 1 H-Pyrrolo[2,3- c]pyridin Derivatives as Potent and Reversible Lysine Specific Demethylase 1 Inhibitors for the Treatment of Acute Myelogenous Leukemia

  • J Med Chem. 2024 Dec 26;67(24):22080-22103. doi: 10.1021/acs.jmedchem.4c02017.
Hong Jiang 1 2 3,  Cong Li 4,  Na Li 2 3 5 6,  Li Sheng 4,  Jingkai Wang 1 2 3,  Wei-Juan Kan 4,  Yuelei Chen 2,  Dongmei Zhao 1,  Dong Guo 7,  Yu-Bo Zhou 4 8,  Bing Xiong 2 3 9,  Jia Li 4 8 9,  Tongchao Liu 2 3
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, P. R. China.
  • 2 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 Lingang Laboratory, Shanghai200031, China.
  • 6 School of Physical Science and Technology, ShanghaiTech University, Shanghai200031, China.
  • 7 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, No. 209, Tongshan Road, Yunlong District, Xuzhou, Jiangsu Province 221004, China.
  • 8 Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica, ChineseAcademy of Sciences, Zhongshan, Guangdong 528400, China.
  • 9 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China.
PMID: 39630953 DOI: 10.1021/acs.jmedchem.4c02017
Abstract

Lysine-specific demethylase 1 (LSD1) plays a vital role in the epigenetic regulation of various cancers, making it a promising therapeutic target for Anticancer treatments. Herein, we designed and synthesized a novel series of 1H-pyrrolo[2,3-c]pyridin derivatives as potent LSD1 inhibitors. A detailed structure-activity relationship exploration was carried out to discover multiple derivatives with nanomolar enzymatic IC50 values. Further biological evaluation demonstrated that these compounds acted as selective and reversible LSD1 inhibitors. The representative compounds exhibited highly potent antiproliferative activity against both AML (MV4-11 and Kasumi-1) and SCLC (NCI-H526) cell lines. Additionally, they effectively activated CD86 mRNA expression in MV4-11 cells and induced differentiation of AML cell lines. Notably, the most promising compound 23e showed a favorable oral PK profile and effectively suppressed the tumor growth in an AML xenograft model. Overall, our medicinal chemistry efforts provide compound 23e as a lead compound for developing LSD1 inhibitors for the treatment of AML and Other advanced malignancies.

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