更新于：2024-11-01

PIM1 x IRAK4

更新于：2024-11-01

基本信息

关联

项与 PIM1 x IRAK4 相关的药物

KIC-0101

靶点

IRAK4 x PIM1

作用机制

IRAK4抑制剂 [+1]

在研机构

Korea Research Institute of Chemical Technology

原研机构

Korea Research Institute of Chemical Technology

在研适应症

弥漫性大B细胞淋巴瘤 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PIM1 x IRAK4 相关的临床结果

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100 项与 PIM1 x IRAK4 相关的转化医学

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0 项与 PIM1 x IRAK4 相关的专利（医药）

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项与 PIM1 x IRAK4 相关的文献（医药）

2023-03-01·Acta Pharmaceutica Sinica B

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

Article

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

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.

2009-11-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Characterization of Novel Diaryl Oxazole-Based Compounds as Potential Agents to Treat Pancreatic Cancer

3区 · 医学

Article

作者: Dorr, Robert T. ; Hurley, Laurence H. ; Henderson, Meredith C. ; Stratton, Steve P. ; Shaw, Arthur Y. ; Han, Haiyong ; Flynn, Gary ; Samulitis, Betty ; Chow, H.-H. Sherry

A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 muM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases.