2. Academic Validation
  3. Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models

Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models

  • Inflamm Res. 2024 Jun 15. doi: 10.1007/s00011-024-01904-6.
Hye Suk Baek # 1,  Victor Sukbong Hong # 2,  Hyunsu Kang # 3 4,  Sang-Jin Lee 5,  Jin-Young Lee 5,  Hyunju Kang 6,  Seungik Jeong 7,  Hyunho Jung 2,  Jong Wook Park 1 8,  Taeg Kyu Kwon 1 8 9,  Chang-Nam Son 10,  Sang Hyon Kim 11,  Jinho Lee 12,  Ki-Suk Kim 13,  Shin Kim 14 15 16
Affiliations

Affiliations

  • 1 Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea.
  • 2 Department of Chemistry, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea.
  • 3 R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
  • 4 Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
  • 5 Department of Biological Sciences, Keimyung University, Daegu, 42601, Republic of Korea.
  • 6 Department of Food and Nutrition, Keimyung University, Daegu, 42601, Republic of Korea.
  • 7 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
  • 8 Institute of Medical Science, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea.
  • 9 Institute for Cancer Research, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea.
  • 10 Department of Rheumatology, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, 712, Dongil-ro, Uijeongbu-si, 11759, Gyeonggi-do, Republic of Korea.
  • 11 Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea.
  • 12 Department of Chemistry, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea. jinho@kmu.ac.kr.
  • 13 R&D Center for Advanced Pharmaceuticals & Evaluation, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea. idkks@kitox.re.kr.
  • 14 Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea. god98005@dsmc.or.kr.
  • 15 Institute of Medical Science, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea. god98005@dsmc.or.kr.
  • 16 Institute for Cancer Research, School of Medicine, Keimyung University, 1095 Dalgubeol-daero, Daegu, 42601, Republic of Korea. god98005@dsmc.or.kr.
  • # Contributed equally.
PMID: 38879731 DOI: 10.1007/s00011-024-01904-6
Abstract

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/β, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and Caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, Cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

Keywords

Inflammation; Macrophage; NLRP3 inflammasome; Osteoclast differentiation; Protein kinase; Rheumatoid arthritis.

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