An interactomics discovery platform for high value intractable cancer drug targets

功能基因组学领域将遗传变异与功能大规模联系起来，已经发现了高度验证和高价值药物靶点的新前沿。例如，有大量证据表明，特定蛋白质的扩增或突变构成癌症进展的直接机制驱动因素，并且这些变体相应地与不良临床结果和治疗抗性高度相关。新兴的靶点包括众所周知的致癌转录因子（如Myc）或信号枢纽（如K-Ras），它们已成为药物发现的焦点;然而，大多数也已被证明通过常规发现方法持续非常困难或不可能药物。这些下一代高价值靶点通常被称为“难治性”或“不可治疗性”，并在药物发现科学的前沿提出了挑战。您将开发一个新的通用化学蛋白质组学技术平台，可以全面探索和询问活癌细胞中任何难治性靶点的相互作用组。因此，您将解锁筛选大型化合物库的小分子的能力，这些小分子选择性地靶向调节每个棘手目标的蛋白质复合物，揭示新类别药物的起点。我们预计您将发现利用只能在完整细胞中发现的新型和癌症特异性作用模式的化合物，包括所谓的“分子胶”模式，其降解或稳定具有难治性靶标的新型或天然复合物。您将在未来药物发现的这一重要领域发展深入而广泛的专业知识，包括化学探针设计，化学蛋白质组学，邻近标记，高通量筛选和CRISPR-Cas技术。

The field of functional genomics, which associates genetic variants with function at a massive scale, has uncovered a new frontier of highly validated and high-value drug targets. For example, there is extensive evidence that amplification or mutation of specific proteins constitutes a direct mechanistic driver of cancer progression, and these variants are correspondingly highly correlated with poor clinical outcome and therapy resistance. Emerging targets include well-known oncogenic transcription factors (e.g. Myc) or signalling hubs (e.g. K-Ras) which have become an intense focus for drug discovery; however, the majority have also proven persistently very difficult or impossible to drug through conventional discovery approaches. These next generation high-value targets are often termed 'intractable' or 'undruggable' and present a challenge at the cutting-edge of drug discovery science.You will develop a new and universal chemical proteomic technology platform which can comprehensively explore and interrogate the interactome for any intractable target in living cancer cells. You will thereby unlock the ability to screen large compound libraries for small molecules which selectively target protein complexes regulating each intractable target, revealing starting points for new classes of medicines. We anticipate that you will discover compounds which exploit novel and cancer-specific modes of action which can only be discovered in the context of an intact cell, including so-called 'molecular glue' modalities which degrade or stabilize novel or native complexes with intractable targets. You will develop a deep and wide range of expertise in this essential area for future drug discovery, including chemical probe design, chemical proteomics, proximity labelling, high-throughput screening and CRISPR-Cas technologies.