Related Experiment Video
Updated: May 2, 2026
Single Molecule Analysis of Laser Localized Psoralen Adducts
Published on: April 20, 2017
Discovery of the DNA-PKcs inhibitor DA-143 which exhibits enhanced solubility relative to NU7441
Zachary J Waldrip1,2, Baku Acharya3, Daniel Armstrong3
1Division of Surgical Research, Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
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.
Insights
A novel DNA-PKcs inhibitor, DA-143, shows improved solubility and enhanced DNA-PKcs inhibition compared to existing drugs. This breakthrough offers potential for more effective cancer and immune disease treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is crucial for DNA repair and immune cell function.
- DNA-PKcs is a therapeutic target for cancer and immune diseases, with inhibitors in early clinical trials.
- Current DNA-PKcs inhibitors face limitations due to poor bioavailability, hindering clinical efficacy.
Purpose of the Study:
- To develop novel DNA-PKcs inhibitors with enhanced bioavailability.
- To evaluate the efficacy and properties of a new inhibitor, DA-143, against existing compounds like NU7441.
Main Methods:
- Synthesis and characterization of novel DNA-PKcs inhibitors.
- Assessment of aqueous solubility and in vitro DNA-PKcs inhibition (IC50).
- Evaluation of DA-143's impact on tumor cell sensitivity to DNA-damaging agents and human T cell function.
Main Results:
- DA-143 demonstrated superior aqueous solubility compared to NU7441 and other inhibitors.
- DA-143 exhibited potent DNA-PKcs inhibition with an IC50 of 2.5 nM, outperforming NU7441.
- DA-143 treatment increased tumor cell sensitivity to chemotherapy and inhibited human T cell function, consistent with DNA-PKcs inhibition.
Conclusions:
- DA-143 represents a promising DNA-PKcs inhibitor with significantly improved bioavailability.
- Enhanced solubility of DA-143 is key to potentially improving efficacy at lower doses.
- DA-143 facilitates more robust preclinical and clinical evaluation of DNA-PKcs as a therapeutic target.
Related Concept Videos
01:21Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
01:15Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions