Explore efflux transporter-associated chemoresistance using a chemical biology approach and develop efflux resistant TOPO I inhibitors as ADC payloads

使用化学生物学方法探索外排转运蛋白相关的化学耐药性，并开发外排抗性 TOPO I 抑制剂作为 ADC 有效负载

• 批准号: 2888791
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2888791
• 关键词: Explore; efflux; transporter; associated; chemoresistance

Antibody-drug conjugates (ADCs) are an emerging class of cancer therapeutics that consist of a monoclonal antibody (mAb) connected to a cytotoxic drug via a linker. The antibody component determines the specificity of the ADC by binding to specific cell surface antigens, allowing selective targeting of certain cell types1. The main advantage of ADCs relative to conventional chemotherapeutics is an increased therapeutic window since the cell-targeting properties of antibodies decrease off-target toxicity2. The FDA has approved 11 ADCs to date with majority of them approved for the treatment of liquid tumours and only 3 ADCs have been approved for solid tumours. An appropriate choice of payload is critical to developing a successful ADC for clinical development3. Developability problems such as efflux liability, non-selective toxicity, chemoresistance, poor pharmacokinetic and pharmacodynamic profiles of existing payloads are leading to failures in clinical development. The majority of ADCs currently in clinical evaluation use microtubule inhibitors or DNA damaging agents as the payload, but more recently a significant number of ADCs with Topoisomerase I (TOPO I) inhibitors have entered clinical development due to the approval of Trodelvy R and Enhertu R which utilise Topoisomerase inhibitors SN-38 and Dxd as payloads (Figure 1), respectively4. Camptothecin and its derivatives bind to the TOPO 1/DNA complex to prevent reannealing, which can cause cell death due to the accumulation of partially cleaved DNA5. Both SN-38 and Dxd are Camptothecin analogues and are considered as next generation ADC payloads due to their relatively small-size and lower toxicity compared to microtubule inhibitors and DNA binding agents. However, both SN-38 and Dxd are efflux substrates of P-gp and BCRP efflux pumps which reduces their effectiveness, causing non-selective toxicity and often leading to chemoresistance particularly in cancer stem cells6,7. The Rahman lab at King's College London has developed a proprietary Efflux Resistance Breaker (ERB) Technology that allows modification of chemical scaffolds to reduce their efflux susceptibility while maintaining the on-target activity (Figure 2)8,9. This increases the intracellular concentration of the drugs which can overcome chemoresistance and reduce the likelihood of resistance emergence.The aim of this PhD project is to explore the phenomenon of efflux transporter-associated resistance using a chemical biology approach and produce ERB-modified TOPO I inhibitors that can be further developed as ADC payloads.

抗体 - 药物结合物（ADC）是一类新兴的癌症治疗剂，由通过接头连接到细胞毒性药物的单克隆抗体（MAB）组成。抗体成分通过与特定细胞表面抗原结合，确定ADC的特异性，从而选择性靶向某些细胞类型1。 ADC相对于常规化学治疗剂的主要优势是增加的治疗窗口，因为抗体的细胞靶向特性会降低靶向脱靶毒性2。迄今为止，FDA已批准11个ADC，其中大多数已批准用于治疗液体肿瘤，并且仅批准了3个ADC用于实体瘤。有效载荷的适当选择对于为临床开发开发成功的ADC至关重要3。可发展性问题，例如外排责任，非选择性毒性，化学抗性，差的药代动力学和现有有效载荷的药效学特征，从而导致临床发育失败。目前在临床评估中的大多数ADC使用微管抑制剂或DNA损害剂作为有效载荷，但最近在大量具有拓扑异构酶I（topo I）抑制剂的ADC由于对Trodelvy R和Enhertu r的批准而获得了临床开发，因此pordeltu r and Enhertu risize topoisemerase ins as as as assomerase ins as as as as as as as as as as as assiptors In-sn-sn-sn-sn-sn-388888888888888888888888888888888888888。 Camptothecin及其衍生物与TOPO 1/DNA复合物结合，以防止重新进行重新构化，这可能导致细胞死亡，因为部分裂解的DNA5的积累。 SN-38和DXD都是Camptothecin类似物，与微管抑制剂和DNA结合剂相比，由于其相对较小的尺寸和较低的毒性，因此被视为下一代ADC有效载荷。但是，SN-38和DXD都是P-gp和BCRP外排泵的外排基底物，可降低其有效性，导致非选择性毒性，并且通常导致化学耐药性，尤其是在癌症干细胞中6,7。伦敦国王学院的拉赫曼实验室（Rahman Lab）开发了一种专有的抗外排破坏者（ERB）技术，该技术允许修改化学支架以降低其外排易感性，同时保持靶向活动的活动（图2）8,9。这增加了药物的细胞内浓度，这些药物可以克服化学抗性并降低耐药性出现的可能性。该博士项目的目的是使用化学生物学方法探索外排相关抗性的现象并产生ERB修饰的TOPO I抑制剂，从而可以进一步开发出ADC的启用载荷。