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.

摘要 20年前，格列卫（伊马替尼）在临床上取得了惊人的成功，这似乎开创了一个新时代， 癌症治疗，其中患者肿瘤中的分子缺陷是已知的，并且可以利用 选择性药物设想了一套这样的选择性药物，100多种不同的药物， 根据100个不同潜在缺陷的肿瘤分析，为适当的患者开出处方。 不幸的是，这一愿景并没有实现，而且，只有少数批准的药物靶点对， 个性化药物在肿瘤学中的全部潜力尚未实现。虽然药物如伊马替尼（和 维罗非尼，奥希替尼，和一些其它的）已经是那些癌症亚型的游戏规则改变者（例如， 分别具有Bcr-Abl易位、BRAFV600 E突变和EGFRT 790 M突变的某些癌症类型）， 仍有数百种癌症亚型和数百种可利用的分子缺陷不匹配 吸毒在这一领域，传统药物发现的缓慢进展表明，新的方法是可行的。 需要充分发挥肿瘤靶向治疗的潜力。我的实验室发现了 平台-从化合物合成，到细胞培养，到目标识别，到复杂的动物模型， 到翻译-这导致了4种新型癌症药物获得许可，并在15年内转移到癌症患者身上。 观察结果表明，在人类癌症患者中取得成功的真正选择性药物也表明 在细胞培养中的精确选择性，我们已经鉴定出具有广泛的杀伤活性差异的化合物， 敏感细胞系与非敏感细胞系;通过这种方法，我们已经鉴定了具有以下特征的化合物： > 100倍的选择性，并且已经进展（或正在进展）到人类癌症患者。在工作中， OIA将创造一个前所未有的复杂多样的化合物集合， 这些化合物将通过引入亲电试剂而偏向于抗癌活性。 能够在一组> 100种癌细胞系和正常细胞类型中诱导选择性死亡的化合物将被 通过药物化学优化来改进。顶级化合物将通过两个平行的 轨道，1）发现生物靶点（抗癌选择性的基础），我们的经验表明， 在大多数情况下，这项工作将揭示癌症中新的可利用缺陷，2）翻译进展 通过药代动力学/毒理学/疗效研究和评估免疫系统的能力， 系统，实验需要移动最好的化合物在癌症患者的临床试验。我们有 展示了在高水平上完成此工作流程所有部分的能力，招募了关键的合作者 根据需要通过这个OIA，我们将增加我们的产量2 - 5倍，这意味着发现和开发 在7年OIA期间，有4 - 10个新的癌症药物/靶标对。同样重要的是，这项工作将提供一个蓝图， 其他人可以模仿的成功，这将最终使个性化的潜力得到充分实现。 医学，有数百种药物用于数百种不同的癌症亚型。