4.5 Article

Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs

期刊

ACS MEDICINAL CHEMISTRY LETTERS
卷 12, 期 1, 页码 82-87

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00474

关键词

IRAK4; PROTAC; protein degrader; scaffolding role; diffuse large B-cell lymphoma

资金

  1. Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020228]
  2. Science and Technology Commission of Shanghai Municipality [18431907100]
  3. National Science AMP
  4. Technology Major Project Key New Drug Creation and Manufacturing Program [2018ZX09711002-011-016]
  5. National Natural Science Foundation of China [21702220]

向作者/读者索取更多资源

IRAK4 is a promising therapeutic target for diffuse large B-cell lymphoma, and a potent IRAK4 degrader was discovered to effectively inhibit downstream signaling. Eliminating both the kinase and scaffolding functions of IRAK4 may result in superior and broader efficacy than inhibiting the kinase activity alone.
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 9 was discovered, and it effectively inhibited the activation of downstream NF-kappa B signaling and outperformed the parent compound 1. In addition, compound 9 displayed a substantial advantage in reduction of the viability of OCI-LY10 and TMD8 cells over the parent compound 1. 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.

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