Developing a Suite of Targeted Anticancer Drugs

开发一套靶向抗癌药物

• 批准号: 10734624
• 负责人: Paul Hergenrother
• 金额: $ 51.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2030-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734624
• 关键词: Acceleration; Animal Model; Antineoplastic Agents; Biological; Cancer Patient; Cancer cell line; Cell Culture Techniques; Cell Line; Cessation of life; Chimeric Proteins; Clinical; Clinical Trials; Collection; Complex; Defect; Development; Drug Kinetics; Drug Targeting; Epidermal Growth Factor Receptor; Gleevec; Human; Imatinib; Immune system; Licensing; Malignant Neoplasms; Methods; Molecular; Mutate; Mutation; Normal Cell; Oncology; Output; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Toxicology; Translations; Vision; Work; anti-cancer; anticancer activity; cancer cell; cancer subtypes; cancer therapy; cancer type; cell type; drug discovery; efficacy evaluation; efficacy study; experience; experimental study; neoplastic cell; novel; novel anticancer drug; novel strategies; overexpression; personalized medicine; precision drugs; success; targeted treatment; tumor

Abstract The stunning clinical success of Gleevec (imatinib) two decades ago appeared to usher in a new era for cancer treatment, whereby a molecular defect in a patient’s tumor was known and could be exploited with a selective drug. A suite of such selective drugs were envisioned, 100s of different drugs that could be prescribed to appropriate patients based on tumor profiling of 100s of different potential defects. Unfortunately this vision has not come to pass, and, with only a handful of approved drug-target pairs, the full potential of personalized medicine in oncology has not been realized. While drugs such as imatinib (and vemurafenib, osimertinib, and a few others) have been game-changers for those cancer subtypes (e.g., certain cancer types with Bcr-Abl translocation, BRAFV600E mutation, and EGFRT790M mutation, respectively), there remain 100s of cancer subtypes and hundreds of exploitable molecular defects that are not matched with drugs. The plodding progress of traditional drug discovery in this realm suggests new approaches are needed to fully realize the potential of targeted therapy for oncology. My lab has developed a discovery platform – from compound synthesis, to cell culture, to target identification, to sophisticated animal models, to translation – that has resulted in 4 novel cancer drugs licensed and moving to cancer patients in 15 years. Building off the observation that truly selective drugs that are successful in human cancer patients also show exquisite selectivity in cell culture, we have identified compounds that have wide activity differential for killing sensitive cell lines versus non-sensitive cell lines; through this method we have identified compounds with >100-fold selectivity and that have advanced (or are advancing) to human cancer patients. In work for the OIA we will create an unprecedented collection of complex-and-diverse compounds, with the novel twist that these compounds will be biased for anticancer activity through incorporation of an electrophile. Compounds able to induce selective death in a panel of >100 cancer cell lines and normal cell types will be advanced through medicinal chemistry optimization. Top compounds will then progress through two parallel tracks, 1) discovery of the biological target (basis for the anticancer selectivity), with our experience showing that in most cases this work will reveal novel exploitable defects in cancer, and 2) translational advancement through the pharmacokinetic/toxicology/efficacy studies and assessment of the ability to engage the immune system, experiments needed to move the very best compounds to clinical trials in cancer patients. We have demonstrated the ability to accomplish all parts of this workflow at a high level, enlisting key collaborators as needed. Through this OIA we will increase our output 2-5-fold, meaning the discovery and development of 4-10 novel cancer drug/target pairs during the 7 year OIA. As importantly, this work will provide a blueprint for success that others can mimic, which will ultimately enable full realization of the potential of personalized medicine, with hundreds of drugs for the hundreds of different cancer subtypes.

抽象的 格莱维克（伊马替尼）二十年前的惊人临床成功出现了一个新时代 癌症治疗，因此知道患者肿瘤中的分子缺陷，可以与 选择性药物。设想了一组此类选择性药物，可以是100种不同的药物 根据100种不同潜在缺陷的肿瘤分析，向适当的患者开出规定。 不幸的是，这种愿景并没有实现 个性化医学在肿瘤学中的全部潜力尚未实现。而伊马替尼等药物（和 Vemurafenib，Osimertinib和其他一些）一直是那些癌症亚型的游戏改变者（例如， 具有BCR-ABL易位，BRAFV600E突变和EGFRT790M突变的某些癌症类型） 仍然存在100次癌症亚型和数百个不匹配的可剥削的分子缺陷 用毒品。在这个领域中，传统药物发现的进展表明，新方法是 需要充分意识到有针对性疗法的肿瘤学的潜力。我的实验室已经开发了一个发现 平台 - 从化合物合成到细胞培养，到靶标识别，再到复杂的动物模型， 翻译 - 这导致了4种新型的癌症药物，并在15年内转移给了癌症患者。 建立一个观察结果，即在人类癌症患者中取得成功的真正选择性药物也表明 在细胞培养中，我们已经确定了具有广泛活性差异的化合物，可杀死 敏感的细胞系与非敏感细胞系；通过这种方法，我们已经确定了化合物 > 100倍的选择性，并且已经提高了（或正在前进）到人类癌症患者。在工作中 OIA，我们将创建一个前所未有的复杂和多样性化合物的集合，并具有小说的转折 这些化合物将通过研究亲电体来偏置抗癌活性。 化合物可以在> 100个癌细胞系中诱导选择性死亡，而正常细胞类型将是 通过医学化学优化提出。然后，顶部化合物将通过两个平行 曲目，1）发现生物学目标（抗癌选择性的基础），我们的经验显示 在大多数情况下，这项工作将揭示癌症中新型的可剥削缺陷，2）转化发展 通过药代动力学/毒理学/功效研究以及评估免疫的能力 系统，需要将最佳化合物转移到癌症患者的临床试验中。我们有 证明了能够高级完成此工作流程的所有部分，并参与了关键的合作者 根据需要。通过此OIA，我们将增加输出2-5倍，这意味着发现和开发 在7年OIA期间，有4-10对新型癌症药物/靶对对。重要的是，这项工作将提供蓝图 为了获得其他人可以模仿的成功，这将最终能够充分实现个性化的潜力 药物，数百种不同的癌症亚型有数百种药物。