2. Academic Validation
  3. Discovery of Highly Selective and Potent Macrocyclic JAK2 Inhibitors for the Treatment of MPNs

Discovery of Highly Selective and Potent Macrocyclic JAK2 Inhibitors for the Treatment of MPNs

  • J Med Chem. 2025 Aug 28;68(16):17933-17959. doi: 10.1021/acs.jmedchem.5c01686.
Songhui Qin 1,  Rui Wu 1,  Yang Tian 2 3,  Minghai Tang 1,  Wei Yan 1,  Xiaobo Cen 4,  Lijuan Chen 1,  Tao Yang 4
Affiliations

Affiliations

  • 1 Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center; West China Hospital; Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
  • 2 Department of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610014, China.
  • 3 Medical Research Center, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610031, China.
  • 4 National Chengdu Center for Safety Evaluation of Drugs, West China Hospital of Sichuan University, Chengdu 610041, China.
PMID: 40767151 DOI: 10.1021/acs.jmedchem.5c01686
Abstract

The development of selective JAK2 inhibitors represents a promising therapeutic strategy for MPNs. Building upon the foundation of our first-generation JAK2 Inhibitor, we employed macrocyclization-driven structural optimization to address its off-target limitations. This strategy yielded a novel class of macrocyclic JAK2 inhibitors, with compound 15au emerging as a standout candidate through systematic SAR studies. Compound 15au exhibits potent JAK2 inhibition (IC50 = 2 nM), coupled with enhanced kinase selectivity, demonstrating 89.5-, 80.5-, and 51-fold selectivity over JAK1, JAK3, and Tyk2, respectively. Mechanistic studies confirm its ability to suppress the JAK2/STAT5 signaling pathway. 15au demonstrates good pharmacokinetic properties, achieving high Cmax and AUC0-t. These properties enable remarkable in vivo efficacy, where 15au outperforms both pacritinib and fedratinib in MPN models at lower doses. This work validates macrocyclization as an effective strategy for refining JAK2 inhibitors, simultaneously enhancing kinase selectivity, metabolic stability, and efficacy.

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