Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma

  • Eur J Med Chem. 2021 Oct 5;221:113481. doi: 10.1016/j.ejmech.2021.113481.
Baishan Jiang  1 ,  Jie Jiang  1 ,  Ines H Kaltheuner  2 ,  Amanda Balboni Iniguez  3 ,  Kanchan Anand  2 ,  Fleur M Ferguson  1 ,  Scott B Ficarro  4 ,  Bo Kyung Alex Seong  3 ,  Ann Katrin Greifenberg  2 ,  Sofia Dust  2 ,  Nicholas P Kwiatkowski  1 ,  Jarrod A Marto  4 ,  Kimberly Stegmaier  3 ,  Tinghu Zhang  1 ,  Matthias Geyer  2 ,  Nathanael S Gray  5
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
  • 2. Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
  • 3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; The Broad Institute, Cambridge, MA, 02142, USA.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
  • 5. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA. Electronic address: [email protected].
PMID: 33945934 DOI: 10.1016/j.ejmech.2021.113481
Abstract

Development of inhibitors targeting CDK12/13 is of increasing interest as a potential therapy for cancers as these compounds inhibit transcription of DNA damage response (DDR) genes. We previously described THZ531, a covalent inhibitor with selectivity for CDK12/13. In order to elucidate structure-activity relationship (SAR), we have undertaken a medicinal chemistry campaign and established a focused library of THZ531 analogs. Among these analogs, BSJ-01-175 demonstrates exquisite selectivity, potent inhibition of RNA polymerase II phosphorylation, and downregulation of CDK12-targeted genes in Cancer cells. A 3.0 Å co-crystal structure with CDK12/CycK provides a structural rational for selective targeting of Cys1039 located in a C-terminal extension from the kinase domain. With moderate pharmacokinetic properties, BSJ-01-175 exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft (PDX) mouse model following 10 mg/kg once a day, intraperitoneal administration. Taken together, BSJ-01-175 represents the first selective CDK12/13 covalent inhibitor with in vivo efficacy reported to date.

Keywords
CDK12/13; Covalent inhibitor; Structure-activity relationship.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145072
    BSJ-01-175
    99.88%, CDK12/13 Covalent Inhibitor
    target: CDK
    Research Areas: Cancer