Developing corrector small molecules for reactivation of mutant p53 in cancer

开发用于重新激活癌症中突变 p53 的校正小分子

• 批准号: 10675004
• 负责人: Peter Kaiser
• 金额: $ 16.92万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675004
• 关键词: Academia; Affect; Animal Model; Antineoplastic Agents; Apoptosis; Automobile Driving; Binding; Biochemical; Biological Assay; Biotechnology; Cancer Patient; Cancer cell line; Cell Culture System; Cell Proliferation; Cells; Chemicals; Clinic; Clinical Trials; Covalent Interaction; Cysteine; DNA Binding; DNA Binding Domain; Development; Diagnosis; Dose; Drug Kinetics; Exposure to; Future; Gene Expression; Genes; Goals; Growth; Human; Hypersensitivity; In Vitro; Lead; Length; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Missense Mutation; Modeling; Molecular Conformation; Mus; Mutate; Mutation; Oxidation-Reduction; Oxidative Stress; Perception; Pharmaceutical Preparations; Predisposition; Prevention; Program Development; Property; Proteins; Reporting; Series; Site; Solid Neoplasm; Sulfhydryl Compounds; System; TP53 gene; Testing; Therapeutic; Translations; Tumor Suppression; Tumor Suppressor Proteins; United States; Xenograft Model; cancer cell; cancer therapy; chemical synthesis; drug development; drug-like compound; experience; gain of function; improved; in vivo; mutant; neoplastic cell; novel therapeutic intervention; patient population; personalized cancer therapy; personalized strategies; preclinical evaluation; reconstitution; research clinical testing; side effect; small molecule; success; targeted treatment; therapeutic protein; therapeutic target; tissue culture; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

PROJECT SUMMARY The tumor suppressor protein p53 is the most frequently mutated protein in human cancers. About 600,000 new cancer patients in the United States are diagnosed each year with tumors expressing mutated p53. Most of the mutations associated with p53 are missense mutations that affect one of six hotspot sites in the DNA binding domain. These cancers express full length p53 that has lost tumor suppressor activity, but acquired gain-of-function oncomorphic properties that provide selective advantage to cancer cells. Therapeutic approaches targeting p53 are challenging and require reactivation of mutated p53. Developing such reactivation or corrector drugs is further complicated by very limited experience in pharma, biotech, and academia in this domain. These challenges in exploring novel therapeutic approaches by developing p53 corrector drugs have led to very slow, and limited success in clinical trials with proposed p53 reactivator compounds. However, one can argue that genuine p53 corrector drugs have not yet been tested in the clinic, because in vivo the available compounds (i.e. APR-246 and other thiol reactive molecules) are most likely not acting on mutant p53, but rather exploit redox-sensitivity of cells expressing p53 mutants. Development of genuine p53 mutant corrector drugs that bind p53 and restore a wild-type like conformation/activity in p53 cancer mutants, thus remains a crucial goal with potentially very high impact. We have developed a small molecule series that binds the L1/S3 pocket of mutant p53 and thereby restores DNA binding activity of mutant p53 in a reconstituted purified in vitro system. These results are reflected in induction of p53 target gene expression when cells harboring p53 hotspot mutants are exposed to these compounds. Furthermore, cell proliferation is halted and apoptosis is induced in a p53 mutant dependent manner. Importantly, growth of solid tumors carrying p53 mutants is blocked by this compound series in animal models. Tumors lacking p53 or expressing wild-type p53 are not affected by such treatment. These compounds provide strong support for feasibility to develop drug-like molecules that can restore tumor suppressor activity in p53 hotspot mutants. However, these compounds act in the low micromolar range in cell culture systems and activity needs to be improved to generate lead compounds for drug development. We propose two parallel approaches to achieve this goal. This proposal will generate promising lead compounds for mutant p53 corrector drug development.

项目摘要 肿瘤抑制蛋白p53是人类癌症中最常见的突变蛋白。约60万 在美国，每年都有新的癌症患者被诊断出患有表达突变的p53的肿瘤。最 与p53相关的突变中有一个是错义突变，影响DNA中六个热点位点之一， 结合域这些癌症表达全长p53，其已失去肿瘤抑制活性，但获得了肿瘤抑制活性。 功能获得性肿瘤形态学特性，为癌细胞提供选择性优势。 靶向p53的治疗方法具有挑战性，需要重新激活突变的p53。发展中 由于在制药、生物技术和生物医学领域的经验非常有限， 学术界在这个领域。通过开发p53来探索新的治疗方法的这些挑战 校正剂药物导致了非常缓慢的，在临床试验中有限的成功与拟议的p53再激活剂 化合物.然而，人们可以争辩说，真正的p53校正药物尚未在临床上进行测试， 因为在体内，可用的化合物（即APR-246和其它硫醇反应性分子）很可能不 作用于突变型p53，而是利用表达p53突变体的细胞的氧化还原敏感性。发展 结合p53并恢复p53中野生型样构象/活性的真正p53突变校正剂药物 因此，癌症突变体仍然是具有潜在非常高影响的关键目标。 我们已经开发了一系列小分子，其结合突变型p53的L1/S3口袋，从而恢复突变型p53的功能。 重组纯化体外系统中突变型p53的DNA结合活性。这些结果反映在 当含有p53热点突变体的细胞暴露于这些突变体时， 化合物.此外，在p53突变体依赖性细胞中，细胞增殖停止并诱导凋亡。 方式重要的是，该化合物系列在动物中阻断了携带p53突变体的实体瘤的生长。 模型缺乏p53或表达野生型p53的肿瘤不受这种治疗的影响。这些 化合物为开发可恢复肿瘤的药物样分子的可行性提供了强有力的支持 p53热点突变体的抑制活性。然而，这些化合物在低微摩尔范围内在细胞中起作用， 需要改进培养系统和活性以产生用于药物开发的先导化合物。我们 提出两个并行的方法来实现这一目标。 这一提议将为突变型p53校正剂药物开发产生有前景的先导化合物。