2. Academic Validation
  3. Discovery of the DNA-PKcs inhibitor DA-143 which exhibits enhanced solubility relative to NU7441

Discovery of the DNA-PKcs inhibitor DA-143 which exhibits enhanced solubility relative to NU7441

  • Sci Rep. 2024 Aug 28;14(1):19999. doi: 10.1038/s41598-024-70858-w.
Zachary J Waldrip # 1 2,  Baku Acharya # 3,  Daniel Armstrong 3,  Maha Hanafi 3 4,  Randall R Rainwater 1 2,  Sharon Amole 5,  Madeline Fulmer 5,  Ana Clara Azevedo-Pouly 1 2,  Alaina Burns 5,  Lyle Burdine 1 6,  Brendan Frett 7,  Marie Schluterman Burdine 8 9
Affiliations

Affiliations

  • 1 Division of Surgical Research, Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • 2 Arkansas Children's Research Institute, Little Rock, AR, 72202, USA.
  • 3 Department of Pharmaceutical Science, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11526, Egypt.
  • 5 College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • 6 Department of Transplant Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • 7 Department of Pharmaceutical Science, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. bafrett@uams.edu.
  • 8 Division of Surgical Research, Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. mburdine@uams.edu.
  • 9 Arkansas Children's Research Institute, Little Rock, AR, 72202, USA. mburdine@uams.edu.
  • # Contributed equally.
PMID: 39198533 DOI: 10.1038/s41598-024-70858-w
Abstract

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a vital role in DNA damage repair and lymphocyte function, presenting a significant target in Cancer and immune diseases. Current DNA-PKcs inhibitors are undergoing Phase I/II trials as adjuncts to radiotherapy and chemotherapy in Cancer. Nevertheless, clinical utility is limited by suboptimal bioavailability. This study introduces DNA-PKcs inhibitors designed to enhance bioavailability. We demonstrate that a novel DNA-PKcs inhibitor, DA-143, surpasses NU7441 in aqueous solubility as well as Other available inhibitors. In addition, DA-143 displayed an improvement in DNA-PKcs inhibition relative to NU7441 achieving an IC50 of 2.5 nM. Consistent with current inhibitors, inhibition of DNA-PKcs by DA-143 resulted in increased tumor cell sensitivity to DNA-damage from chemotherapy and inhibition of human T cell function. The improved solubility of DA-143 is critical for enhanced efficacy at reduced doses and facilitates more effective evaluation of DNA-PKcs inhibition in both preclinical and clinical development.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-169121
    DNA-PKcs Inhibitor