2. Academic Validation
  3. 2-Aminopyrimidine derivatives as selective dual inhibitors of JAK2 and FLT3 for the treatment of acute myeloid leukemia

2-Aminopyrimidine derivatives as selective dual inhibitors of JAK2 and FLT3 for the treatment of acute myeloid leukemia

  • Bioorg Chem. 2023 May:134:106442. doi: 10.1016/j.bioorg.2023.106442.
Sicong Xu 1,  Yiran Zhu 1,  Jie Meng 1,  Chao Li 1,  Zhenzhen Zhu 1,  Chen Wang 1,  Yu-Cheng Gu 2,  Liang Han 3,  Jiajie Wen 3,  Minghui Tong 3,  Xuan Shi 3,  Yunlei Hou 1,  Yajing Liu 4,  Yanfang Zhao 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China.
  • 2 Syngenta Jealott's Hill International Research Center, Bracknell, Berkshire RG42 6EY, UK.
  • 3 3D BioOptima, 1338 Wuzhong Avenue, Suzhou 215104, China.
  • 4 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China. Electronic address: lyjpharm@126.com.
  • 5 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, Liaoning 110016, China. Electronic address: yanfangzhao@126.com.
PMID: 36878064 DOI: 10.1016/j.bioorg.2023.106442
Abstract

Dual inhibitors of JAK2 and FLT3 can synergistically control the development of acute myeloid leukemia (AML), and overcome secondary drug resistance of AML that is associated with FLT3 inhibition. We therefore designed and synthesized a series of 4-piperazinyl-2-aminopyrimidines as dual inhibitors of JAK2 and FLT3, and improved their selectivity for JAK2. Screening cascades revealed that compound 11r exhibited inhibitory activity with IC50 values of 2.01, 0.51, and 104.40 nM against JAK2, FLT3, and JAK3, respectively. Compound 11r achieved a high selectivity for JAK2 at a ratio of 51.94, and also showed potent antiproliferative activity in HEL (IC50 = 1.10 μM) and MV4-11 (IC50 = 9.43 nM) cell lines. In an in vitro metabolism assay, 11r exhibited moderate stability in human liver microsomes (HLMs), with a half-life time of 44.4 min, and in rat liver microsomes (RLMs), with a half-life of 143 min. In pharmacokinetic studies, compound 11r showed moderate absorption (Tmax = 5.33 h), with a peak concentration of 38.7 ng/mL and an AUC of 522 ng h/mL in rats, and an oral bioavailability of 25.2%. In addition, 11r induced MV4-11 cell Apoptosis in a dose-dependent manner. These results indicate that 11r is a promising selective JAK2/FLT3 dual inhibitor.

Keywords

2-aminopyrimidine derivatives; Acute myeloid leukemia; FLT3; JAK2; JAK2/FLT3 dual inhibitor.

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