Discovery and validation of novel protein lipidation drug targets in cancer

脂化是一类丰富而广泛的蛋白质翻译后修饰（PTM），在信号传导、细胞死亡、免疫、蛋白质稳定性和运输中起着关键作用。超过150种癌蛋白和潜在的癌症药物靶点被脂化，包括许多不适合传统药物发现的蛋白。干预调节蛋白质脂化的广泛酶网络提供了一个独特的机会来靶向这些“不可药物”的蛋白质，最近FDA在2020年批准了第一个脂质转移酶抑制剂，验证了这种方法。我们开发了化学蛋白质组学技术来研究所有主要类别的蛋白质脂化，并将靶标验证和新型脂化抑制剂用于肿瘤学的临床前开发，于2019年成立Myricx Pharma，将我们的发现转化为一流的治疗药物，造福癌症患者。在这个项目中，我们将与弗朗西斯克里克研究所（Francis Crick Institute）、癌症研究所（ICR）和致力于癌症脂化抑制剂开发的行业的科学家合作，利用现代基因编辑和筛选方法，应用化学探针设计、化学遗传学、蛋白质组学和机制药物靶点验证，以确定和验证癌症治疗的新靶点。

Lipidation is a rich and widespread class of protein post-translational modification (PTM), with key roles in signalling, cell death, immunity, protein stability and trafficking. More than 150 oncoproteins and potential cancer drug targets are lipidated, including many not amenable to traditional drug discovery. Intervening in the extensive network of enzymes regulating protein lipidation presents a unique opportunity to target these 'undruggable' proteins, an approach recently validated with the first FDA approval of a lipid transferase inhibitor in 2020. We have developed chemical proteomic technologies to study all the major classes of protein lipidation and delivered target validation and novel lipidation inhibitors into preclinical development for oncology, founding Myricx Pharma in 2019 to translate our findings into first in class therapeutics to benefit cancer patients. In this project, in collaboration with scientists at the Francis Crick Institute, Institute of Cancer Research (ICR) and in industry working on development of lipidation inhibitors in cancer, we will apply chemical probe design, chemical genetics, proteomics, and mechanistic drug target validation using modern gene editing and screening approaches to identify and validate novel targets for cancer therapy.