An interactomics discovery platform for high value intractable cancer drug targets

功能基因组学将基因变异与大规模的功能联系在一起，揭示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了癌症进展的直接机制驱动因素，这些变异与不良的临床结果和治疗耐药性高度相关。新出现的靶点包括众所周知的致癌转录因子(如Myc)或信号中心(如K-RAS)，它们已成为药物发现的热点；然而，事实证明，大多数药物仍然很难或不可能通过传统的发现方法进行药物治疗。这些新一代的高价值靶点通常被称为“难对付的”或“无法下药的”，这对药物发现科学的前沿提出了挑战。你将开发一个新的通用化学蛋白质组技术平台，它可以全面探索和询问活癌细胞中任何顽固靶点的相互作用组。因此，您将释放筛选大化合物库中小分子的能力，这些小分子选择性地针对调节每个难处理的靶点的蛋白质复合体，揭示新的药物类别的起点。我们预计，您将发现利用只有在完整细胞中才能发现的新颖和癌症特有作用模式的化合物，包括所谓的“分子胶”模式，它可以降解或稳定具有难处理靶点的新的或天然的化合物。您将在这一关键领域为未来的药物发现培养深厚而广泛的专业知识，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.