新型亲电基团在共价不可逆靶向药物和抗体药物共轭物设计中的应用

Recently covalent drugs have been found to be an effective way to treat drug-induced resistance, especially in target therapy for cancer treatments. The key to the success in designing a covalent drug is the choice of the electrophilic groups equipped in the drug. The electrophilicity of the selected group in a covalent drug for target therapy has to be in a suitable range in order for the drug to be stable enough in systemic circulation before reaching the intended target. The current choice is limited to be a Michael acceptor such as acrylamide group, or a disulfide moiety, both of which suffer from selectivity or stability issues and may result in various adverse effects. The research in the proposal focuses on the design of a novel electrophilic group in covalent drugs, especially for several anti-cancer drug targets which contain a cysteine group nearby the ligand binding site, such as BTK, EGFR tyrosine kinase and the cancer causing K-ras G12C mutant. The new covalent drug design strategy has been validated with the successful identification of a novel series of potent irreversible BTK inhibitors. In addition, the reactivity of the electrophilic group will also be studied for conjugating antibodies with small molecule cytotoxic agents for a new antibody-drug conjugate (ADC) design.

近年来，共价结合药物已成为克服药物耐药性治疗的有效途径，尤其是在针对肿瘤的靶向治疗中。成功设计共价结合药物的关键在于合理地选择亲电基团，用于靶向治疗药物的共价结合部分的亲电性需要控制在一定的合理范围内，以保证药物到达靶点前在系统循环中有一定的稳定性。现有策略的主要限于Michael受体，如丙烯酰胺或二硫键片段，然而它们都存在选择性差或稳定性差等缺点，并可能导致严重的副作用。本研究项目拟设计共价结合药物中的新型亲电基团，特别是在配体结合部分存在半胱氨酸（Cys）的抗肿瘤靶点中，如：BTK和导致肿瘤产生的K-ras G12C突变蛋白等。近期，我们的研究设想已在BTK不可逆抑制剂中初步验证了新型亲电片段在共价结合中的有效性和可行性。未来的工作将进一步研究该亲电片段的反应活性，研究运用它作为新一代亲电基团来进行抗肿瘤药物的合理设计。