title: HM71224, a novel Bruton's tyrosine kinase inhibitor, suppresses B cell and monocyte activation and ameliorates arthritis in a mouse model: a potential drug for rheumatoid arthritis.
abstract: BACKGROUND
  Bruton's tyrosine kinase (Btk) is critical for activation of B cells and myeloid cells. This study aimed to characterize the effects of HM71224, a novel Btk inhibitor, both in vitro and in a mouse model of experimental arthritis.
  
  
  METHODS
  The kinase inhibition profile of HM71224 was analyzed. The in vitro effects of HM71224 on B cells and monocytes were analyzed by examining phosphorylation of Btk and its downstream signaling molecules, along with cytokine production and osteoclast formation. The in vivo effects of HM71224 were investigated in a mouse model of collagen-induced arthritis (CIA).
  
  
  RESULTS
  HM71224 irreversibly bound to and inhibited Btk (IC50 = 1.95 nM). The compound also inhibited the phosphorylation of Btk and its downstream molecules such as PLCγ2, in activated Ramos B lymphoma cells and primary human B cells in a dose-dependent manner. Furthermore, HM71224 effectively inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β by human monocytes, and osteoclast formation by human monocytes. Finally, HM71224 improved experimental arthritis and prevented joint destruction in a murine model of CIA.
  
  
  CONCLUSIONS
  HM71224 inhibits Btk in B cells and monocytes and ameliorates experimental arthritis in a mouse model. Thus, HM71224 is a potential novel therapeutic agent for rheumatoid arthritis in humans.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea.
authors.forename: Jin Kyun
authors.initials: JK
authors.lastname: Park
authors.affiliation: Hanmi Research Center, Hanmi Pharm.Co., Ltd., 550 Dongtangiheung-ro, Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea.
authors.forename: Joo-Yun
authors.initials: JY
authors.lastname: Byun
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea.
authors.forename: Ji Ah
authors.initials: JA
authors.lastname: Park
authors.affiliation: Hanmi Research Center, Hanmi Pharm.Co., Ltd., 550 Dongtangiheung-ro, Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea.
authors.forename: Yu-Yon
authors.initials: YY
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea.
authors.forename: Ye Ji
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Hanmi Research Center, Hanmi Pharm.Co., Ltd., 550 Dongtangiheung-ro, Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea.
authors.forename: Jeong In
authors.initials: JI
authors.lastname: Oh
authors.affiliation: Hanmi Research Center, Hanmi Pharm.Co., Ltd., 550 Dongtangiheung-ro, Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Jang
authors.affiliation: Hanmi Research Center, Hanmi Pharm.Co., Ltd., 550 Dongtangiheung-ro, Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea.
authors.forename: Yeong Wook
authors.initials: YW
authors.lastname: Song
authors.affiliation: Hanmi Pharm.Co., Ltd., 45 Bangi-dong, Songpa, Seoul, Gyeonggi-do, 138-724, Republic of Korea.
authors.forename: Jeewoong
authors.initials: J
authors.lastname: Son
authors.affiliation: Hanmi Research Center, Hanmi Pharm.Co., Ltd., 550 Dongtangiheung-ro, Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea.
authors.forename: Kwee Hyun
authors.initials: KH
authors.lastname: Suh
authors.affiliation: Hanmi Research Center, Hanmi Pharm.Co., Ltd., 550 Dongtangiheung-ro, Hwaseong-si, Gyeonggi-do, 18469, Republic of Korea. leeym@hanmi.co.kr.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehank-no Chongno-gu, Seoul, 03080, Korea. leb7616@snu.ac.kr.
authors.forename: Eun Bong
authors.initials: EB
authors.lastname: Lee
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D009000:Monocytes / Q000276:immunology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse
keywords: B cells; Btk inhibitor; HM71224; Inflammation; Monocytes; Osteoclast; Rheumatoid arthritis