PMID- 33761599 OWN - NLM STAT- MEDLINE DCOM- 20210720 LR - 20240226 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 137 DP - 2021 May TI - Studies on the anti-psoriasis effects and its mechanism of a dual JAK2/FLT3 inhibitor flonoltinib maleate. PG - 111373 LID - S0753-3322(21)00158-X [pii] LID - 10.1016/j.biopha.2021.111373 [doi] AB - Psoriasis is a chronic, inflammatory autoimmune disease mediated by T cells, and characterized with abnormal proliferation and differentiation of keratinocytes, and inflammatory infiltration. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway has been identified to play essential roles in mediating various of biological processes, and is closely related to autoimmune diseases. Dendritic cells (DCs) are important antigen presenting cells and play an important regulatory role in T cells. The proliferation, differentiation and function of DCs are regulated by JAK and FMS-like tyrosine kinase 3 (FLT3) signal pathways. Flonoltinib maleate (FM), a high selectivity dual JAK2/FLT3 inhibitor with IC(50) values of 0.8 nM and 15 nM for JAK2 and FLT3, respectively, was developed by our laboratory. Moreover, FM was a potent JAK2 inhibitor with 863-fold and 696-fold selectivity over JAK1 and JAK3, respectively. In this study, the anti-psoriasis activity of FM was evaluated both in vitro and in vivo. FM effectively inhibited the proliferation of HaCaT, the inflammatory keratinocyte induced by M5 and markedly suppressed the generation and differentiation of DCs from bone marrow (BM), and inhibited the expression of FLT3 in DCs in vitro. FM effectively inhibited the ear thickening and improved the pathological changes of the ear in interleukin (IL)-23-induced psoriasis-like acanthosis mouse model. Further in keratin 14-vascular endothelial growth factor (K14-VEGF) transgenic homozygous mice model, FM could obviously improve the psoriatic symptom and pathological changes, significantly inhibit the generations of Th1 and Th17 cells in the spleen, and the accumulations of DCs in the ears. FM could also significantly reduce the expression of various inflammatory factors both in C57BL/6 and K14-VEGF mice ears, and the serum of K14-VEGF mice. Mechanism revealed that FM effectively suppressed the phosphorylation of JAK2, STAT3 and STAT5 in inflammatory keratinocytes and the mice ears of C57BL/6 and K14-VEGF, as well as the phosphorylation of FLT3 in K14-VEGF mice ears. In conclusion, FM plays an excellent anti-psoriasis activity, including inhibiting keratinocyte proliferation and regulating inflammatory response through inhibiting JAK2 and FLT3 signaling pathway. CI - Copyright (c) 2021. Published by Elsevier Masson SAS. FAU - Zhu, Jiali AU - Zhu J AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Yang, Tao AU - Yang T AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Tang, Minghai AU - Tang M AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Yang, Zhuang AU - Yang Z AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Pei, Heying AU - Pei H AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Ye, Haoyu AU - Ye H AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Tang, Yu AU - Tang Y AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Cheng, Zhixuan AU - Cheng Z AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Lin, Ping AU - Lin P AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. FAU - Chen, Lijuan AU - Chen L AD - State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: chenlijuan125@163.com. LA - eng PT - Journal Article DEP - 20210224 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Protein Kinase Inhibitors) RN - 0 (STAT Transcription Factors) RN - EC 2.7.10.1 (Flt3 protein, mouse) RN - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) RN - EC 2.7.10.2 (Jak2 protein, mouse) RN - EC 2.7.10.2 (Janus Kinase 2) SB - IM MH - Animals MH - Bone Marrow Cells/drug effects MH - Cell Line MH - Cell Proliferation/drug effects MH - Dendritic Cells/drug effects MH - Ear, External/drug effects MH - Humans MH - Janus Kinase 2/*antagonists & inhibitors MH - Keratinocytes/drug effects MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Protein Kinase Inhibitors/pharmacology MH - Psoriasis/*drug therapy MH - STAT Transcription Factors/drug effects/genetics MH - Signal Transduction/*drug effects MH - fms-Like Tyrosine Kinase 3/*antagonists & inhibitors MH - Mice OTO - NOTNLM OT - DCs OT - FLT3 OT - Flonoltinib maleate (FM) OT - Inflammation OT - JAK-STAT signal pathway OT - Psoriasis EDAT- 2021/03/26 06:00 MHDA- 2021/07/21 06:00 CRDT- 2021/03/25 01:01 PHST- 2020/11/19 00:00 [received] PHST- 2021/01/25 00:00 [revised] PHST- 2021/02/02 00:00 [accepted] PHST- 2021/03/25 01:01 [entrez] PHST- 2021/03/26 06:00 [pubmed] PHST- 2021/07/21 06:00 [medline] AID - S0753-3322(21)00158-X [pii] AID - 10.1016/j.biopha.2021.111373 [doi] PST - ppublish SO - Biomed Pharmacother. 2021 May;137:111373. doi: 10.1016/j.biopha.2021.111373. Epub 2021 Feb 24.