A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway

作     者：Sae-Bom Yoon Hyowon Hong Hee-Jong Lim Ji Hye Choi Yoon Pyo Choi Seong Wook Seo Hyuk Woo Lee Chong Hak Chae Woo-Kyu Park Hyun Young Kim Daeyoung Jeong Tran Quang De Chang-Seon Myung Heeyeong Cho Sae-Bom Yoon;Hyowon Hong;Hee-Jong Lim;Ji Hye Choi;Yoon Pyo Choi;Seong Wook Seo;Hyuk Woo Lee;Chong Hak Chae;Woo-Kyu Park;Hyun Young Kim;Daeyoung Jeong;Tran Quang De;Chang-Seon Myung;Heeyeong Cho

作者机构：Therapeutics&Biotechnology DivisionKorea Research Institute of Chemical TechnologyYuseong-guDaejeon 34114Republic of Korea Department of PharmacologyChungnam National University College of PharmacyYuseong-guDaejeon 34134Republic of Korea Future Medicine Co.Ltd.Rm616 LH-Business Growth CenterSeongnamGyeonggido 13449Republic of Korea Department of ChemistryCollege of Natural SciencesCan Tho UniversityCan Tho city 9000Viet Nam 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第3期

页      面：1093-1109页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by a grant from the Korea Research Institute of Chemical Technology(KRICT,South Korea,project number SI-2231-40,KK1963-413) 3D-TissueChip Based Drug Discovery Platform Technology Development Program(20009774,High-Throughput 3D Multifunctional Tissue-based Screening Service of Efficacy and Safety for Drug Discovery)funded by the Ministry of Trade,Industry and Energy(MOTIE,South Korea) 

主　　题：Drug discovery IRAK4 PIM1 NF-κB pathway Rheumatoid arthritis ABC-DLBCL Ibrutinib resistance Dual inhibitor 

摘      要：Interleukin-1 receptor-associated kinase 4(IRAK4)is a pivotal enzyme in the Toll-like receptor(TLR)/MYD88 dependent signaling pathway,which is highly activated in rheumatoid arthritis tissues and activated B cell-like diffuse large B-cell lymphoma(ABC-DLBCL).Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of ***,proviral integration site for Moloney murine leukemia virus 1(PIM1)functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib *** developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in *** rheumatoid arthritis mouse models,treatment with KIC-0101 significantly ameliorated cartilage damage and ***-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in *** addition,KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-κB pathway and PIM1 *** results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.