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 二十年前格列卫（伊马替尼）取得的惊人临床成功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 设想了一套这样的选择性药物，可能有数百种不同的药物。 根据数百种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， 虽然伊马替尼（和）等药物尚未充分发挥肿瘤学中个性化医疗的潜力。 维莫非尼（vemurafenib）、奥希替尼（osimertinib）和其他一些药物）已经改变了这些癌症亚型（例如， 某些癌症类型分别具有 Bcr-Abl 易位、BRAFV600E 突变和 EGFRT790M 突变）， 仍然有数百种癌症亚型和数百种可利用的分子缺陷不匹配 传统药物发现在这一领域的缓慢进展表明新的方法正在出现。 需要充分发挥肿瘤学靶向治疗的潜力 我的实验室已经取得了一项发现。 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， 到转化——这使得 4 种新型抗癌药物在 15 年内获得许可并用于癌症患者。 建立在对人类癌症患者取得成功的真正选择性药物的观察基础上，还表明 在细胞培养中具有精湛的选择性，我们已经鉴定出具有广泛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，我们鉴定了化合物 > 100 倍的选择性，并且已经进展（或正在进展）为人类癌症患者工作。 OIA 我们将创造前所未有的复杂多样的化合物系列，并具有新颖的转折 这些化合物将通过掺入亲电子试剂而偏向于抗癌活性。 能够诱导超过 100 种癌细胞系和正常细胞类型选择性死亡的化合物 然后，顶级化合物将通过两个平行的过程进行进展。 跟踪，1）生物靶标的发现（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，以及 2）转化进展 通过药代动力学/毒理学/功效研究和免疫参与能力评估 我们有系统，需要进行实验才能将最好的化合物转移到癌症患者的临床试验中。 在高水平上展示完成此工作流程所有部分的能力，招募关键合作者 根据需要，通过 OIA，我们的产量将增加 2-5 倍，这意味着发现和开发。 在 7 年的 OIA 期间开发 4-10 个新型癌症药物/靶点对 同样重要的是，这项工作将提供一个蓝图。 获得其他人可以模仿的成功，这最终将充分实现个性化的潜力 医学，有数百种药物用于治疗数百种不同的癌症亚型。