深度解读：自身免疫病与癌症的“双料靶点”——IRAK4研究格局盘点

Core Viewpoint - Targeting IRAK4 is a promising therapeutic strategy for autoimmune diseases and cancer, given its central role in inflammation and immune regulation [2][3][13] Group 1: IRAK4 Structure and Function - IRAK4 is a serine/threonine kinase involved in innate immune regulation, playing a critical role in various inflammation-related signaling pathways [2][3] - It is positioned at the core of the IL-1R/TLR signaling pathway, activating key signals that initiate the expression of inflammatory factors [4][6] Group 2: Role in Diseases - Chronic inflammation mediated by IRAK4 is linked to diseases such as rheumatoid arthritis, systemic lupus erythematosus, and cancer, where it promotes tumor growth and immune suppression [4][6] - The abnormal activation of IRAK4 can lead to chronic inflammation and contribute to the progression of malignancies [4][6] Group 3: Clinical Development of IRAK4 Inhibitors - There are currently 20 IRAK4 candidate drugs in clinical research globally, including single-target inhibitors, multi-target inhibitors, and PROTAC degraders [8][9] - Notable candidates include Zimlovisertib (Phase II) for rheumatoid arthritis and COVID-19 pneumonia, and Emavusertib (Phase II) for hematologic malignancies [9] Group 4: Challenges in Development - The development of IRAK4 inhibitors faces challenges, as seen with Pfizer's Zimlovisertib and Bayer's Zabedosertib, which were terminated due to insufficient efficacy in specific conditions [11] - Multi-target inhibitors are gaining attention, with companies exploring combinations with other targets like BTK and FLT3, particularly in hematological cancers [11] Group 5: PROTAC Degraders - IRAK4 degraders using the PROTAC approach not only inhibit kinase activity but also selectively degrade IRAK4, blocking its scaffold function [12] - Clinical trials are ongoing for several PROTAC candidates, such as KT-474 for atopic dermatitis and HS, showing promising results in preclinical studies [12]