2. Academic Validation
  3. Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies

Discovery of Novel 2-Aminopyridine-Based and 2-Aminopyrimidine-Based Derivatives as Potent CDK/HDAC Dual Inhibitors for the Treatment of Refractory Solid Tumors and Hematological Malignancies

  • J Med Chem. 2024 Sep 12;67(17):15220-15245. doi: 10.1021/acs.jmedchem.4c00837.
Abdusaid Saidahmatov 1 2,  Jianan Li 3,  Shihao Xu 1 2,  Xiaobei Hu 1 4,  Xiangqian Gao 3,  Weijuan Kan 1,  Lixin Gao 1,  Cong Li 1,  Yuqiang Shi 1,  Li Sheng 1,  Peipei Wang 1,  Yubo Zhou 1 2 4,  Xuewu Liang 1 2,  Jia Li 1 2 3 4 5,  Hong Liu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District, Guangdong 528400, China.
  • 5 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
PMID: 39178382 DOI: 10.1021/acs.jmedchem.4c00837
Abstract

Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell Apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful Apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent Anticancer activity.

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