Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Chemical Society
      Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
    • Subject Terms:
      Cyclin-Dependent Kinases*/antagonists & inhibitors ; Cyclin-Dependent Kinases*/metabolism ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/pharmacokinetics ; Biological Availability* ; Proteolysis*/drug effects; Humans ; Animals ; Cell Line, Tumor ; Rats ; Administration, Oral ; Cell Proliferation/drug effects ; Mice ; Female ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/pathology ; Drug Discovery ; Xenograft Model Antitumor Assays ; Rats, Sprague-Dawley ; Mice, Nude ; Structure-Activity Relationship ; CDC2 Protein Kinase
    • Abstract:
      Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of ZLC491 as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader. The compound effectively degraded CDK12 and CDK13 with DC 50 values of 32 and 28 nM, respectively, in TNBC MDA-MB-231 cells. Global proteomic assessment and mechanistic studies revealed that ZLC491 selectively induced CDK12/13 degradation in a cereblon- and proteasome-dependent manner. Furthermore, the molecule efficiently suppressed transcription and expression of long genes, predominantly a subset of genes associated with DNA damage response, and significantly inhibited proliferation of multiple TNBC cell lines. Importantly, ZLC491 achieved an oral bioavailability of 46.8% in rats and demonstrated potent in vivo degradative effects on CDK12/13 in an MDA-MB-231 xenografted mouse model.
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    • Grant Information:
      P50 CA186786 United States CA NCI NIH HHS; R35 CA231996 United States CA NCI NIH HHS
    • Accession Number:
      EC 2.7.11.22 (CDK12 protein, human)
      EC 2.7.11.22 (Cyclin-Dependent Kinases)
      0 (Antineoplastic Agents)
      EC 2.7.11.22 (CDK13 protein, human)
      EC 2.7.11.22 (CDC2 Protein Kinase)
    • Publication Date:
      Date Created: 20241010 Date Completed: 20241024 Latest Revision: 20241030
    • Publication Date:
      20241031
    • Accession Number:
      PMC11513923
    • Accession Number:
      10.1021/acs.jmedchem.4c01596
    • Accession Number:
      39388374