2. Academic Validation
  3. Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy

Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy

  • J Med Chem. 2023 Jun 8;66(11):7454-7474. doi: 10.1021/acs.jmedchem.3c00176.
Yi-Qian Li 1 2,  William G Lannigan 2,  Shabnam Davoodi 1 2,  Fereidoon Daryaee 1 2,  Ana Corrionero 3,  Patricia Alfonso 3,  Jose A Rodriguez-Santamaria 3,  Nan Wang 1 2,  John D Haley 4,  Peter J Tonge 1 2 5
Affiliations

Affiliations

  • 1 Center for Advanced Study of Drug Action, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
  • 2 Department of Chemistry, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
  • 3 Enzymlogic S.L., QUBE Technology Park, C/ Santiago Grisolía, 2, Madrid 28760, Spain.
  • 4 Department of Pathology, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-8691, United States.
  • 5 Department of Radiology, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
PMID: 37195170 DOI: 10.1021/acs.jmedchem.3c00176
Abstract

Bruton's tyrosine kinase (Btk) is a target for treating B-cell malignancies and autoimmune diseases, and several Btk inhibitors are already approved for use in humans. Heterobivalent Btk protein degraders are also in development, based on the premise that proteolysis targeting chimeras (PROTACs) may provide additional therapeutic benefits. However, most BTK PROTACs are based on the Btk Inhibitor ibrutinib raising concerns about their selectivity profiles, given the known off-target effects of ibrutinib. Here, we disclose the discovery and in vitro characterization of BTK PROTACs based on the selective Btk Inhibitor GDC-0853 and the Cereblon recruitment ligand pomalidomide. PTD10 is a highly potent Btk degrader (DC50 0.5 nM) that inhibited cell growth and induced Apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, and had improved selectivity compared to ibrutinib-based BTK PROTACs.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-154860
    PROTAC BTK降解剂
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