2. Academic Validation
  3. Discovery of novel selective phosphodiesterase‑1 inhibitors for the treatment of acute myelogenous leukemia

Discovery of novel selective phosphodiesterase‑1 inhibitors for the treatment of acute myelogenous leukemia

  • Bioorg Chem. 2024 Mar:144:107114. doi: 10.1016/j.bioorg.2024.107114.
Mei-Ling Le 1,  Yi-Yi Yang 2,  Mei-Yan Jiang 2,  Chuan Han 2,  Zhi-Rong Guo 3,  Run-Duo Liu 2,  Zheng-Jiong Zhao 2,  Qian Zhou 4,  Shijun Wen 5,  Yinuo Wu 6
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, Hainan, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
  • 6 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: [email protected].
PMID: 38224637 DOI: 10.1016/j.bioorg.2024.107114
Abstract

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger Apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced Apoptosis. Further experiments indicated that the Apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of Caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

Keywords

Acute myelogenous leukemia; Apoptosis; Phosphodiesterase-1.

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