Unlocking new drug targets through antibody-targeted protein degradation

利用蛋白水解靶向嵌合体（Proteolysis-Targeting Chimeras, PROTACs）靶向蛋白质降解是当前药物发现的一个重要领域。然而，尽管PROTACs可以对多种靶标非常有效，但迄今为止报道的大多数降解物表现出有限的内在组织选择性，并且不能区分不同类型的细胞。我们最近报道了一种在特定细胞类型中选择性蛋白降解的新策略，其中一种抗体- protac偶联物，证明了her2阳性乳腺癌细胞特异性靶蛋白的抗原依赖性降解（ACS Chem）。生物学报，2020,1306)。这些研究证明了组织特异性降解的概念验证，克服了PROTAC选择性的局限性，具有应用于新靶标的巨大潜力。该项目将靶向蛋白质降解方面的创新与ADC Therapeutics在临床前和临床抗体-药物偶联物（ADC）开发方面的世界领先专业知识（https://www.adctherapeutics.com/）结合在一起，以发现新一代靶向蛋白质降解物作为新型ADC有效载荷。您将推动ADC设计的边界，开发新的模式，包括高亲和力的基于多肽的降解物，用于棘手的目标，分子胶，自噬或溶酶体靶向化合物。您将把这些有效载荷与临床级ADC连接器设计和单克隆抗体相结合，以精确释放针对各种疾病适应症的特定组织类型的降解物，最初的重点是癌症。该奖学金将适合有才华和积极进取的化学家或化学生物学家，他们对生物医学界面的研究充满热情，并对靶向蛋白质降解和新型药物模式有浓厚的兴趣。申请人应在化学或相关领域有杰出的学术背景。将提供所有相关领域的培训（合成、生物偶联、细胞生物学等），但有合成、化学生物学或蛋白质化学方面的实验室经验者优先。成功的申请人将在1.7亿英镑的最先进的分子科学研究中心和位于帝国理工学院新白城校区的I-HUB的ADC Therapeutics进行研究。

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although PROTACs can be highly effective against a wide variety of targets, most degraders reported to date display limited intrinsic tissue selectivity, and do not discriminate between cells of different types. We recently reported a novel strategy for selective protein degradation in a specific cell type with one of the first antibody-PROTAC conjugates, demonstrating antigen-dependent degradation of a target protein specifically in HER2-positive breast cancer cells (ACS Chem. Biol. 2020, 1306). These studies demonstrated proof-of-concept for tissue-specific degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.This project brings together innovations in targeted protein degradation with the world-leading expertise of ADC Therapeutics in preclinical and clinical antibody-drug conjugate (ADC) development (https://www.adctherapeutics.com/) to discover a new generation of targeted protein degraders as novel ADC payloads. You will push the boundaries of ADC design, exploiting new modalities including high-affinity peptide-based degraders for intractable targets, molecular glues, and autophagy- or lysosome-targeting compounds. You will combine these payloads with clinical grade ADC linker design and monoclonal antibodies to enable precise release of degraders targeted to specific tissue types across a range of disease indications, with an initial focus on cancer.This studentship would suit a talented and motivated chemist or chemical biologist who is passionate about research at the interface with biomedicine, and with a strong interest in targeted protein degradation and novel drug modalities. Applicants should have an outstanding academic background in chemistry or a closely related area. Training will be provided in all relevant areas (synthesis, bioconjugations, cell biology, etc.), but previous lab experience in synthesis, chemical biology or protein chemistry would an advantage. The successful applicant will undertake research at the £170M state-of-the-art Molecular Sciences Research Hub and with ADC Therapeutics at the I-HUB, co-located at Imperial's new White City Campus.