2. Academic Validation
  3. Discovery of Janus Kinase and Histone Deacetylase Dual Inhibitors as a New Strategy to Treat Psoriasis

Discovery of Janus Kinase and Histone Deacetylase Dual Inhibitors as a New Strategy to Treat Psoriasis

  • J Med Chem. 2024 Nov 14;67(21):19267-19281. doi: 10.1021/acs.jmedchem.4c01681.
Weijie Hu 1,  Jing Shen 2,  Chenchen Zhou 2,  Zongguang Tai 3,  Quangang Zhu 3,  Zhongjian Chen 3,  Yahui Huang 2,  Chunquan Sheng 1 2
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou 325035, Zhejiang, People's Republic of China.
  • 2 The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, People's Republic of China.
  • 3 Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, People's Republic of China.
PMID: 39415349 DOI: 10.1021/acs.jmedchem.4c01681
Abstract

Psoriasis is a common, chronic, recurrent, and inflammatory skin disease, which causes physical and psychological problems in patients and lacks effective and economic therapeutics. Herein, we designed Janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors as a new strategy for the treatment of psoriasis. In particular, compound 11i was identified with excellent inhibitory activity toward JAKs (JAK2 IC50 = 0.49 nM) and HDACs (HDAC6 IC50 = 12 nM). Moreover, it exhibited potent activities in inhibiting the proliferation of TNF-α-induced HaCAT cells and the production of nitric oxide. Importantly, compound 11i significantly ameliorated psoriasis-like skin lesions in an imiquimod-induced murine model with low toxicity, which was superior to JAK Inhibitor momelotinib, HDAC Inhibitor vorinostat, and their combination. This work provided a proof-of-concept for JAK/HDAC dual inhibitors as a promising strategy for the treatment of psoriasis.

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