2. Academic Validation
  3. Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL

Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL

  • J Med Chem. 2021 Aug 12;64(15):10878-10889. doi: 10.1021/acs.jmedchem.1c00103.
Liqiang Fu 1,  Jing Zhang 2,  Bin Shen 2,  Linglong Kong 1,  Yingtao Liu 1,  Wangyang Tu 1,  Wenqian Wang 2,  Xin Cai 3,  Xiaotao Wang 3,  Na Cheng 2,  Mingxuan Xia 2,  Tianyuan Zhou 2,  Qian Liu 1,  Yanping Xu 1,  Jennifer Yang 2,  Paul Gavine 2,  Ulrike Philippar 4,  Ricardo Attar 5,  James P Edwards 6,  Jennifer D Venable 6,  Xuedong Dai 7 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Janssen Research & Development, Shanghai 201210, China.
  • 2 Department of Biology, Janssen Research & Development, Shanghai 201210, China.
  • 3 Department of Biomarker, Janssen Research & Development, Shanghai 201210, China.
  • 4 Janssen Pharmaceutical Research & Development, Beerse 2340, Belgium.
  • 5 Janssen Pharmaceutical Research & Development, Spring House, Pennsylvania 19477, United States.
  • 6 Discovery Sciences, Janssen Research & Development, San Diego, California 92121, United States.
  • 7 Discovery Sciences, Janssen (China) Research & Development, Shanghai 201210, P.R. China.
PMID: 34279092 DOI: 10.1021/acs.jmedchem.1c00103
Abstract

MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.

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