1957236-20-2Relevant articles and documents
Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands
Bricelj, Ale?a,Dora Ng, Yuen Lam,Ferber, Dominic,Gütschow, Michael,Kr?nke, Jan,Kuchta, Robert,Müller, Sina,Monschke, Marius,Sosi?, Izidor,Steinebach, Christian,Wagner, Karl G.
supporting information, p. 1733 - 1738 (2021/11/16)
Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides a blueprint for the assembly of future heterodimeric CRBN-based degraders with tailored properties.
Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation
Zhang, Jing,Fu, Liqiang,Shen, Bin,Liu, Yingtao,Wang, Wenqian,Cai, Xin,Kong, Linglong,Yan, Yilin,Meng, Ryan,Zhang, Zhuming,Chen, Ying-Nan P.,Liu, Qian,Wan, Zhao-Kui,Zhou, Tianyuan,Wang, Xiaotao,Gavine, Paul,Del Rosario, Amanda,Ahn, Kay,Philippar, Ulrike,Attar, Ricardo,Yang, Jennifer,Xu, Yanping,Edwards, James P.,Dai, Xuedong
, p. 1500 - 13,1509 (2020/10/02)
The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.Zhang and Fu et al. developed a series of IRAK4 degraders designed from an IRAK4-selective kinase inhibitor to deconvolute IRAK4 kinase and scaffolding functions in ABC DLBCL cells. Interestingly, neither kinase inhibition nor protein degradation affected cell proliferation or apoptosis, suggesting a redundant role of IRAK4 in ABC DLBCL.
