Targeting KRAS mutant cancers using a novel inhibitor of PLK1 substrate binding

癌症是一种由调节细胞生长和存活的关键基因突变引起的遗传疾病。近年来，新的“靶向”疗法旨在从功能上逆转癌症的根本遗传原因，在许多癌症类型中取得了成功。然而，胰腺肿瘤，一种特别致命的癌症形式，并没有从这些进步中受益;主要是由于难以“药物”其主要的驱动基因，称为“KRAS”。PhoreMost开发了一种策略，使我们能够通过开发一流的抑制剂来绕过这种直接给药问题，这些抑制剂结合到一个单独但已确立的癌症临床靶点（PLK 1）中的一个新位点，该靶点显示出与突变KRAS的先前未被认识到的组合“合成致死性”。在这项资助中，我们将优化这些化合物的效力和选择性，然后测试它们在体内的功效，如果成功，我们将与一家制药公司合作，在临床试验中进行进一步测试。

Cancer is a genetic disease caused by mutations in key genes that regulate cell-growth and survival. In recent years, new ‘targeted’ therapies that aim to functionally reverse the root genetic causes of cancer have shown success in many cancer types. However Pancreatic tumours, a particularly lethal form of cancer, has not benefited from such advances; primarily due to the difficulty in ‘drugging’ its predominant driver-gene called ‘KRAS’. PhoreMost has developed a strategy that allows us to bypass this direct drugging problem by developing first-in-class inhibitors that bind to a novel site in a separate but well established cancer clinical target (PLK1), which display a previously unappreciated combined 'synthetic lethality' with mutant KRAS. In this grant we be optimising the potency and selectivity of these compounds and then testing them for their efficacy in vivo, which if successful we will partner with a pharmaceutical company for further testing in clinical trials.