A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway.
- Author:
Sae-Bom YOON
1
;
Hyowon HONG
1
;
Hee-Jong LIM
1
;
Ji Hye CHOI
1
;
Yoon Pyo CHOI
2
;
Seong Wook SEO
2
;
Hyuk Woo LEE
2
;
Chong Hak CHAE
1
;
Woo-Kyu PARK
1
;
Hyun Young KIM
1
;
Daeyoung JEONG
1
;
Tran Quang DE
1
;
Chang-Seon MYUNG
3
;
Heeyeong CHO
1
Author Information
- Publication Type:Journal Article
- Keywords: ABC-DLBCL; Drug discovery; Dual inhibitor; IRAK4; Ibrutinib resistance; NF-κB pathway; PIM1; Rheumatoid arthritis
- From: Acta Pharmaceutica Sinica B 2023;13(3):1093-1109
- CountryChina
- Language:English
- Abstract: 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 lymphoma. Moreover, proviral integration site for Moloney murine leukemia virus 1 (PIM1) functions as an anti-apoptotic kinase in propagation of ABC-DLBCL with ibrutinib resistance. We developed a dual IRAK4/PIM1 inhibitor KIC-0101 that potently suppresses the NF-κB pathway and proinflammatory cytokine induction in vitro and in vivo. In rheumatoid arthritis mouse models, treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation. KIC-0101 inhibited the nuclear translocation of NF-κB and activation of JAK/STAT pathway in ABC-DLBCLs. 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 kinase. Our results suggest that KIC-0101 is a promising drug candidate for autoimmune diseases and ibrutinib-resistant B-cell lymphomas.
