Chemical bioreductive approaches to targeted radiosensitisation and imaging of tumours

肿瘤靶向放射增敏和成像的化学生物还原方法

• 批准号: MR/N009460/1
• 负责人: Stuart Conway
• 金额: $ 89.52万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN009460%2F1
• 关键词: Chemical; bioreductive; approaches; targeted; radiosensitisation

All cells in the human body require oxygen to survive. The condition where insufficient oxygen is available, as occurs in heart attacks and strokes for example, is referred to as hypoxia.The human body is designed to resist the formation of tumours, so any developing tumour faces many challenges, one of which is oxygen supply. Unfortunately, tumours manage to overcome this challenge and cheat the body into providing oxygen to a greater or lesser extent.The tumour cells, which receive insufficient oxygen and experience hypoxia, adapt to this condition and in so doing become stronger and more difficult to kill.In particular, hypoxic tumour cells are more resistant to radiotherapy than tumour cells that receive sufficient oxygen.Clearly, as 50% off all people treated for cancer receive radiotherapy, it is important to find ways of making this treatment more effective against hypoxic tumour cells. Presently, the more hypoxic the cancer the less effective is the radiotherapy treatment.This new work is a collaboration between the Chemistry Department and Oncology at Oxford who together have come up with a way to tackle hypoxic tumour cells.So far, the chemists have made a drug, which can kill hypoxic tumour cells and make them more susceptible to radiotherapy, but does not harm normal cells. The biologists have tested this drug on hypoxic human cancer cells grown in the laboratoryAs a next step, we would like to be able to make more of this new drug and to test it further both in the laboratory and in mice. This kind of testing is essential if this drug is ever going to progress to being useful in combination with radiotherapy for cancer patients. We also plan to modify the drug so that it becomes fluorescent as soon as it becomes active in hypoxic conditions. This will make the biological testing much easier as we will be able to see exactly when and where it becomes active.In summary, the more hypoxic a tumour is the more likely it is to kill the patient. Therefore, our approach to target these cells specifically could have a major impact on patient survival.

人体内的所有细胞都需要氧气才能生存。缺乏氧气的情况，例如心脏病发作和中风，被称为低氧。人体天生就能抵抗肿瘤的形成，所以任何正在发展的肿瘤都面临着许多挑战，氧气供应就是其中之一。不幸的是，肿瘤成功地克服了这一挑战，或多或少地欺骗了身体提供氧气。接受氧气不足和经历低氧的肿瘤细胞适应这种情况，在这样做的过程中变得更强大和更难杀死。尤其是，低氧肿瘤细胞比获得足够氧气的肿瘤细胞对放射治疗的抵抗力更强。显然，由于所有接受癌症治疗的人中有50%接受放射治疗，找到方法使这种治疗对低氧肿瘤细胞更有效是很重要的。目前，癌症越缺氧，放射治疗的效果就越差。这项新工作是由化学系和牛津大学肿瘤学合作完成的，他们共同提出了一种解决缺氧肿瘤细胞的方法。到目前为止，化学家们已经制造出一种药物，可以杀死缺氧的肿瘤细胞，使它们更容易受到放射治疗的影响，但不会损害正常细胞。生物学家已经在实验室培养的低氧人类癌细胞上测试了这种药物。作为下一步，我们希望能够制造更多这种新药，并在实验室和小鼠身上进一步测试它。如果这种药物要在癌症患者的放射治疗中发挥作用，这种测试是必不可少的。我们还计划对药物进行改造，使其在低氧条件下一变得活跃就变得荧光。这将使生物测试变得容易得多，因为我们将能够准确地看到它在何时何地变得活跃。总而言之，肿瘤越低氧，就越有可能导致患者死亡。因此，我们以这些细胞为靶点的方法可能会对患者的生存产生重大影响。

项目成果

The Design, Synthesis, and Evaluation of Hypoxia-Activated Prodrugs of the KDAC Inhibitor Panobinostat

KDAC 抑制剂帕比司他缺氧激活前药的设计、合成和评价

• DOI: 10.26434/chemrxiv.13502706.v1
• 发表时间: 2020
• 作者: Calder E

Hypoxia-Activated Pro-Drugs of the KDAC Inhibitor Vorinostat (SAHA)

KDAC 抑制剂伏立诺他 (SAHA) 的缺氧激活前药

• DOI: 10.26434/chemrxiv.9963503.v1
• 发表时间: 2019
• 作者: Calder E

Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.

ATR的药理抑制可以通过非ATR独立的机制阻止自噬。

• DOI: 10.1016/j.isci.2020.101668
• 发表时间: 2020-11-20
• 期刊: iScience
• 影响因子: 5.8
• 作者: Bowler E;Skwarska A;Wilson JD;Ramachandran S;Bolland H;Easton A;Ostheimer C;Hwang MS;Leszczynska KB;Conway SJ;Hammond EM
• 通讯作者: Hammond EM

BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability.

BET 布罗莫结构域配体：探测 WPF 架以提高 BRD4 布罗莫结构域亲和力和代谢稳定性。

• DOI: 10.1016/j.bmc.2018.05.003
• 发表时间: 2018
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Jennings LE