2. Academic Validation
  3. Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase

Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase

  • J Med Chem. 2020 Sep 24;63(18):10460-10473. doi: 10.1021/acs.jmedchem.0c01125.
Sébastien L Degorce 1,  Omid Tavana 2,  Erica Banks 2,  Claire Crafter 3,  Lakshmaiah Gingipalli 1,  David Kouvchinov 4,  Yumeng Mao 3,  Fiona Pachl 4,  Anisha Solanki 3,  Viia Valge-Archer 3,  Bin Yang 1,  Scott D Edmondson 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
  • 2 Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.
  • 3 Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge Science Park, Unit 310 Darwin Building, Cambridge CB4 0WG, U.K.
  • 4 Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Boston, 35 Gatehouse Drive, Waltham, MA, United States.
PMID: 32803978 DOI: 10.1021/acs.jmedchem.0c01125
Abstract

We report the first disclosure of IRAK3 degraders in the scientific literature. Taking advantage of an opportune byproduct obtained during our efforts to identify IRAK4 inhibitors, we identified ready-to-use, selective IRAK3 ligands in our compound collection with the required properties for conversion into proteolysis-targeting chimera (PROTAC) degraders. This work culminated with the discovery of PROTAC 23, which we demonstrated to be a potent and selective degrader of IRAK3 after 16 h in THP1 cells. 23 induced proteasome-dependent degradation of IRAK3 and required both CRBN and IRAK3 binding for activity. We conclude that PROTAC 23 constitutes an excellent in vitro tool with which to interrogate the biology of IRAK3.

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