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发现 DNA-PKcs 抑制剂 DA-143 与 NU7441 相比具有增强的溶解性。

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

机构信息

Division of Surgical Research, Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

Arkansas Children's Research Institute, Little Rock, AR, 72202, USA.

出版信息

Sci Rep. 2024 Aug 28;14(1):19999. doi: 10.1038/s41598-024-70858-w.

DOI:10.1038/s41598-024-70858-w
PMID:39198533
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11358143/
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 IC 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.

摘要

DNA 依赖性蛋白激酶催化亚基 (DNA-PKcs) 在 DNA 损伤修复和淋巴细胞功能中发挥着重要作用，是癌症和自身免疫性疾病的重要靶点。目前，DNA-PKcs 抑制剂正在进行 I/II 期临床试验，作为癌症放疗和化疗的辅助药物。然而，由于生物利用度不理想，其临床应用受到限制。本研究介绍了旨在提高生物利用度的 DNA-PKcs 抑制剂。我们证明了一种新型的 DNA-PKcs 抑制剂 DA-143 在水溶解度以及其他可用抑制剂方面均优于 NU7441。此外，与 NU7441 相比，DA-143 对 DNA-PKcs 的抑制作用有所改善，IC50 达到 2.5 nM。与现有的抑制剂一致，DA-143 抑制 DNA-PKcs 导致肿瘤细胞对化疗引起的 DNA 损伤更加敏感，并抑制人 T 细胞功能。DA-143 的溶解度提高对于降低剂量时提高疗效至关重要，并有助于在临床前和临床开发中更有效地评估 DNA-PKcs 抑制作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/00f6f2bc127d/41598_2024_70858_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/a412077ba4d5/41598_2024_70858_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/f5c6c041dd80/41598_2024_70858_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/a3ba3224aec5/41598_2024_70858_Sch2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/bc66eea9d439/41598_2024_70858_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/ac4e10554d3a/41598_2024_70858_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/df6d973b4370/41598_2024_70858_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/74be43985a01/41598_2024_70858_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/00f6f2bc127d/41598_2024_70858_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/a412077ba4d5/41598_2024_70858_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/f5c6c041dd80/41598_2024_70858_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/a3ba3224aec5/41598_2024_70858_Sch2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/bc66eea9d439/41598_2024_70858_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/ac4e10554d3a/41598_2024_70858_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/df6d973b4370/41598_2024_70858_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/74be43985a01/41598_2024_70858_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/29fc/11358143/00f6f2bc127d/41598_2024_70858_Fig6_HTML.jpg

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