KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia

急性骨髓性白血病（AML）是一种从骨髓开始并进入血液的癌症。抵抗感染和调节血液凝固的血细胞的损失经常导致败血症或严重出血。这种癌症在老年人群（65岁以上）中最常见，并且难以治疗。目前的疗法是相对粗糙的化学治疗“大锤”，并且不是广泛有效的和/或耐受性差，特别是对于老年人。这导致超过70%的65岁以上的患者在诊断后的第一年内死亡，只有不到15%的患者能活过5年。卡迪夫大学的药物发现研究所开发了一种新型治疗药物，可以彻底改变这种疾病的治疗方法，并治疗所有AML患者，在脆弱的老年人群中具有良好的耐受性。我们将通过靶向体内一种称为KAT 2A的特定蛋白质来实现这一目标，该蛋白质在阻止人体识别和摧毁癌细胞方面起着关键作用。我们的方法利用了一种新技术，使我们能够利用细胞内人体自身的分子废物处理系统来去除这种靶蛋白。这一解决方案在5年前是不可想象的，但现在为我们提供了一个机会，可以推动一种技术解决方案，可以广泛使用，并且比目前的治疗毒性更小。我们的项目背后有多年的发现努力，并完成了广泛的优化和表征活动，以确定三种有潜力进入临床试验的先进分子。现在，我们需要进一步研究这些分子，以完成监管机构要求的数据包，并选择这些分子中最好的作为潜在的新疗法。这些研究将为我们的新型分子确定最佳剂量，并告诉我们如何最好地使用这些分子来帮助患者。这些实验显著增强了专注于为这一患者群体开发新癌症治疗方法的团体的进一步投资潜力。

Acute Myeloid Leukaemia (AML) is a form of cancer that starts in the bone marrow and moves into the blood. The loss of blood cells to fight infection and to mediate blood clotting frequently leads to sepsis or significant hemorrhage. This cancer is most common in the older population (over 65 years) and is difficult to treat. Current therapies are relatively crude chemotherapeutic "sledgehammers" and are not widely effective and/or are poorly tolerated, particularly by the elderly. This leads to over 70% of patients over 65 years old dying within the first year of diagnosis and fewer than 15% living beyond year 5. The Medicines Discovery Institute at Cardiff University has developed a novel therapeutic agent which can revolutionise treatment of this disease and treat all AML patients, with the potential to be well tolerated in the vulnerable elderly population. We will do this by targeting a specific protein in the body, known as KAT2A, which plays a key role in blocking the body from recognising and destroying the cancer cells.Our approach has exploited a novel technology that allows us to harness the body's own molecular waste disposal systems within the cell to remove this target protein. This solution was unimaginable 5 years ago, but now presents us with the opportunity to advance a technology solution that could be widely used and would be less toxic than current treatments.Our project has many years of discovery effort behind it, and has completed an extensive campaign of optimisation and characterisation to identify three advanced molecules which have the potential to progress into clinical trials. Now, we need to further study these molecules to complete the data package that is required by regulatory agencies and to select the best of these molecules as the potential new therapy. These studies will establish the best dose to use for our novel molecules and inform us on how best to use these molecules to help patients. These experiments significantly enhance the potential for onward investment by groups focused on the development of new cancer treatments for this patient population.