Chen Yun, Ning Yi, Bai Gang, Tong Linjiang, Zhang Tao, Zhou Jinpei, Zhang Huibin, Xie Hua, Ding Jian, Duan Wenhu
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. China.
ACS Med Chem Lett. 2020 Dec 10;12(1):82-87. doi: 10.1021/acsmedchemlett.0c00474. eCollection 2021 Jan 14.
Interleukin-1 receptor associated kinase 4 (IRAK4) is a promising therapeutic target for diffuse large B-cell lymphoma driven by MYD88 L265P mutant, acting both as a kinase and a scaffolding protein for downstream signaling molecules. While previous efforts to modulate IRAK4 activity with kinase inhibitors alone displayed moderate efficacy, protein degradation may offer a solution to blocking both IRAK4 kinase activity and scaffolding capabilities. To this end, the potent IRAK4 degrader was discovered, and it effectively inhibited the activation of downstream NF-κB signaling and outperformed the parent compound . In addition, compound displayed a substantial advantage in reduction of the viability of OCI-LY10 and TMD8 cells over the parent compound . These results underline the potential that eliminating both the kinase and scaffolding functions of IRAK4 may result in superior and broader efficacy than inhibiting the kinase activity alone.
白细胞介素-1受体相关激酶4（IRAK4）是由MYD88 L265P突变驱动的弥漫性大B细胞淋巴瘤的一个有前景的治疗靶点，它既作为一种激酶，又作为下游信号分子的支架蛋白。虽然之前单独使用激酶抑制剂调节IRAK4活性的努力显示出中等疗效，但蛋白质降解可能为阻断IRAK4激酶活性和支架功能提供一种解决方案。为此，发现了强效的IRAK4降解剂，它有效抑制了下游NF-κB信号的激活，并且比母体化合物表现更优。此外，在降低OCI-LY10和TMD8细胞活力方面，化合物比母体化合物具有显著优势。这些结果强调了消除IRAK4的激酶和支架功能可能比单独抑制激酶活性产生更优、更广泛疗效的潜力。
