Therapeutic Potential and Mechanism of Action of Potent Small Molecule Inhibitors

有效小分子抑制剂的治疗潜力和作用机制

• 批准号: 7892546
• 负责人: SHAOMENG WANG
• 金额: $ 22.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7892546
• 关键词: Affinity; Apoptosis; Binding; Cancer Biology; Cancer cell line; Cell Cycle Arrest; Cell Death; Cell Death Induction; Cell Line; Cisplatin; Clinical Trials; Collaborations; Complex; Data; Development; Double Minutes; Drug Kinetics; Foundations; Funding; Future; Goals; Gossypol; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Homologous Gene; Human; In Vitro; Lead; MDM2 gene; MDM2 gene; Malignant Squamous Cell Neoplasm; Mediating; Molecular; Molecular Mechanisms of Action; Mus; Mutate; National Cancer Institute; Normal Cell; Oral; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Prevention; Proteins; Reproduction spores; Resistance; Resolution; Solid; Specificity; Structure; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Tumor Tissue; Xenograft procedure; analog; base; cancer cell; cell growth; design; effective therapy; in vitro activity; in vivo; inhibitor/antagonist; novel therapeutics; overexpression; small molecule; treatment strategy; tumor; tumor growth

Cisplatin (CDDP) is a primary agent for the treatment of head and neck squamous cell cancers (HNSCC). During the previous funding period, our group has established that HNSCC cells resistant to CDDP are characterized by high expression of Bcl-xL and wild type p53. Based upon our data, we hypothesize that agents designed to inhibit Bcl-xL or activate p53 function can be highly effective strategies for the treatment of CDDP-resistant HNSCC. To date, we have evaluated a small-molecule inhibitor of Bcl-xL ((-)-gossypol) as a potential novel therapeutic agent for the treatment of HNSCC. Our in vitro and in vivo studies have formed the scientific basis for a future clinical trial of (-)-gossypol in collaboration with Ascenta Therapeutics and the National Cancer Institute. In this new SPORE project, we propose to test a novel therapeutic strategy to target CDDP-resistant HNSCC cells with wild-type p53 status using a potent and specific smallmolecule inhibitor of the MDM2-p53 interaction. In HNSCC cells with wild type p53, the function of p53 is effectively inhibited by its endogenous cellular inhibitor, the MDM2 (or HDM2) protein. MDM2 is transcriptionally activated by p53 and in turn, inhibits p53 activity through multiple mechanisms mediated by direct binding to p53. MDM2 thus functions as a potent and highly effective endogenous inhibitor of p53. We hypothesize that blocking of the interaction between MDM2 and p53 using a potent small-molecule inhibitor can effectively reactivate p53 function in HNSCC cells with wild type p53, which will lead to cell cycle arrest and apoptosis. Design and development of non-peptide, drug-like, small molecule inhibitors to target the MDM2-p53 interaction is an exciting and new therapeutic strategy for the treatment of CDDPresistant HNSCC with wild type p53. Based upon the high-resolution crystal structure of MDM2 in complex with the p53 peptide, we have designed a class of highly potent, non-peptide, small-molecule inhibitors of the MDM2-p53 interaction using an effective structure-based strategy. The most potent small-molecule nhibitor has a Ki value of 2 nM binding to MDM2 protein, 1000-times more potent than the natural p53 peptide. Using a potent lead compound (MI-63) and its inactive control analogue, we have already demonstrated that MI-63 is highly effective in inhibition of cell growth and induction of cell death in HNSCC cancer cell lines with wild-type p53 and displays an excellent selectivity over HNSCC cancer cell lines with mutated p53 status. Moreover, using an isogenic cell line transfected with Bcl-xL protein, we also show that overexpression of Bcl-xL has no effect upon the activity of potent MDM2 inhibitors, in contrast to CDDP. Based upon our preliminary results, we hypothesize that a potent and specific small-molecule inhibitor of the MDM2-p53 will be developed as a new and highly effective therapy for the treatment of HNSCC, either as a single agent or in combination with other therapies.

顺铂（CDDP）是治疗头颈鳞状细胞癌（HNSCC）的主要药物。 在上一个资金期间，我们的小组确定HNSCC细胞对CDDP有抗性 以Bcl-XL和野生型p53的高表达为特征。根据我们的数据，我们假设 旨在抑制BCL-XL或激活p53功能的代理可能是治疗的高效策略 耐CDDP的HNSCC。迄今为止，我们已经评估了Bcl-XL的小分子抑制剂（（ - gossypol） 作为治疗HNSCC的潜在新型治疗剂。我们的体外和体内研究具有 与Ascenta Therapeatics合作（ - gossypol）的将来的临床试验构成了科学基础 和国家癌症研究所。在这个新的孢子项目中，我们建议测试一种新颖的治疗性 使用有效的小分子靶向具有野生型p53状态的耐CDDP HNSCC细胞的策略 MDM2-P53相互作用的抑制剂。在具有野生型p53的HNSCC细胞中，p53的功能为 通过其内源性细胞抑制剂MDM2（或HDM2）蛋白有效抑制。 MDM2是 通过p53激活并通过多种机制介导的多种机制来抑制p53活性 直接结合到p53。因此，MDM2充当p53的有效且高效的内源性抑制剂。 我们假设使用有效的小分子阻止MDM2和p53之间的相互作用 抑制剂可以有效地激活具有野生型p53的HNSCC细胞中的p53功能，这将导致细胞 周期停滞和凋亡。非肽，类似药物的小分子抑制剂的设计和开发 目标MDM2-P53相互作用是一种令人兴奋的新治疗策略 HNSCC带有野生型p53。基于复合物中MDM2的高分辨率晶体结构 使用p53肽，我们设计了一类高效，非肽，小分子抑制剂 使用有效的基于结构的策略的MDM2-P53相互作用。最有效的小分子 NHIBOTOR具有与MDM2蛋白的2 nm结合，比天然p53高1000倍 肽。使用有效的铅化合物（MI-63）及其无效的控制类似物，我们已经 证明MI-63在抑制细胞生长和HNSCC细胞死亡的诱导方面非常有效 具有野生型p53的癌细胞系，对HNSCC癌细胞系具有出色的选择性 突变的p53状态。此外，使用用Bcl-XL蛋白转染的同基因细胞系，我们还表明 与CDDP相比，BCl-XL的过表达对有效的MDM2抑制剂的活性没有影响。 基于我们的初步结果，我们假设一种有效的特定小分子抑制剂 MDM2-P53将作为一种用于治疗HNSCC的新的高效疗法，即 作为单个代理或与其他疗法结合使用。