A Chemical Genetic Approach to Exploring Novel Therapeutic Space for Colorectal Cancer

探索结直肠癌新治疗空间的化学遗传学方法

• 批准号: 10182641
• 负责人: Ross Leigh Cagan
• 金额: $ 63.51万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10182641
• 关键词: Animals; Apoptosis; BRAF gene; Benchmarking; Biological Assay; Biology; Cancer Etiology; Cancer Model; Cells; Cessation of life; Chemical Modifier; Chemicals; Chemistry; Clinical; Colorectal Cancer; Complex; Computer Models; Data; Development; Diagnosis; Disease; Drosophila genus; Drug Design; Drug Kinetics; Epidermal Growth Factor Receptor; Excretory function; FDA approved; Genetic; Genetic Screening; Goals; Half-Life; Human; Immunotherapy; In Vitro; KRAS2 gene; Lead; Libraries; Malignant Neoplasms; Maps; Mediating; Metabolism; Modeling; Modification; Monomeric GTP-Binding Proteins; Mus; Nature; Neoplasm Metastasis; Oncogenic; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Primary carcinoma of the liver cells; Property; Protein Isoforms; RAF1 gene; Refractory; Series; Signal Transduction; Structure; Structure-Activity Relationship; Survival Rate; TP53 gene; Testing; Therapeutic; Therapeutic Index; Toxic effect; Treatment Efficacy; United States; Variant; Xenograft Model; Xenograft procedure; absorption; analog; aurora kinase A; base; chemical genetics; colon cancer cell line; colon cancer patients; comparative; cost; design; drug development; fly; gastrointestinal; genetic analysis; genetic approach; improved; in vivo; inhibitor/antagonist; innovation; insight; interdisciplinary approach; kinase inhibitor; metastatic colorectal; mortality; mutant; neoplastic cell; network attack; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; side effect; small molecule; structural biology; tumor; tumor growth

Project Summary Metastatic colorectal cancer (mCRC) is the second leading cause of cancer-related mortality in the United States, and annually accounts for nearly 500,000 deaths worldwide. Currently, the small molecule kinase inhibitor (KI) regorafenib is the primary second line therapy for metastatic CRC that is not treatable with immunotherapy or anti-EGFR therapies. However, regorafenib generally provides only modest improvements in survival— typically months—and often at the cost of significant side effects. Proposed targets for regorafenib include kinases that act within tumor cells as well as non-autonomously; however, with over 500 possible targets in the human kinome, the exact mechanism by which this compound operates remains controversial and not fully known. This presents a daunting challenge; without a verifiable target or mechanism, no clear path exists to guide the development of improved therapies for mCRC. Here, we propose an alternative approach to drug development that focuses on kinase networks in the context of the whole animal. Specifically, we will take a multidisciplinary approach to define kinases that are beneficial to inhibit (‘pro-targets’) or avoid (‘anti-targets’) in the context of KRAS-variant CRC. Using Drosophila and mammalian models, we will identify kinases that—when reduced—alter the efficacy of regorafenib and similar compounds. We will also conduct extensive structure-activity relationship analyses, evaluating how modifications in already identified lead compounds impact changes in efficacy and therapeutic index. Finally, we will use computational structural biology to convert our chemical genetic insights into highly optimized and precise polypharmacological leads. In this final step, we generate new analogs to selectively eliminate putative anti-target activity while maintaining or increasing inhibitory activity against other beneficial targets. We have used our chemical genetic platform to identify a promising lead compound, APS5-86-2, that demonstrates significant activity relative to regorafenib in several mCRC models, including human patient derived xenografts (PDX). Comparative analysis suggests that the improved activity of APS5-86-2 relative to regorafenib derives from distinct polypharmacology on several RTKs and critical cancer drivers, including CDK9, AURKA, EGFR, BRAF, and RAF1. In this proposal, we examine the mechanism and importance of these and other putative pro- and anti-target kinases using genetic analysis and in vivo target engagement. The objective is to identify the kinase networks that mediate KRAS-variant mCRC by combining chemical biology with genetics, and to then derive inhibitors that best attack these networks through structure-based drug design. We have been successful previously with a similar approach, but in less complex tumor models (Dar et al., Nature, 2012; Sonoshita et al., Nature Chem. Bio., 2018); here we seek to extend our platform to a more prevalent disease with the goal of directly impacting mCRC by creating new, highly differentiated, and improved drugs.

项目摘要 转移性结直肠癌（MCRC）是联合癌症相关死亡率的第二大原因 各州，全世界将近500,000人死亡。目前，小分子激酶 抑制剂（Ki）雷伐尼是转移性CRC的主要第二线治疗，无法用 免疫疗法或抗EGFR疗法。但是，Regorafenib通常仅提供适度的改进 生存（通常是几个月），并且通常是出于重大副作用而造成的。提议的雷戈非尼目标 包括在肿瘤细胞中作用以及非自主的激酶；但是，有超过500个可能的目标 在人类的主体中，该化合物运作的确切机制仍然存在争议，而不是 完全知道。这提出了艰巨的挑战；没有可验证的目标或机制，就不存在明确的路径 指导改进的MCRC疗法的发展。 在这里，我们提出了一种替代药物开发的方法，该方法专注于激酶网络 整个动物的背景。具体来说，我们将采用一种多学科的方法来定义激酶 在Kras-Variant CRC的背景下，有益于抑制（'Pro-targets'）或避免（“反目标”）。使用果蝇 和哺乳动物的模型，我们将确定激酶（减少）的激酶，以改变恢复和恢复的效率 类似的化合物。我们还将进行广泛的结构 - 活动关系分析，评估如何 已经确定的铅化合物的修改会影响效率和治疗指数的变化。最后，我们 将使用计算结构生物学将我们的化学遗传见解转化为高度优化和 精确的多药学铅。在最后一步中，我们生成新的类似物以选择性地消除推定 在维持或增加对其他有益靶标的抑制活性的同时，抗目标活性。 我们已经使用化学遗传平台来识别有希望的铅化合物APS5-86-2， 在包括人类患者在内 衍生的异种移植物（PDX）。比较分析表明，相对于APS5-86-2的活性提高了 再丙替尼在几个RTK和关键的癌症驱动因素上源自不同的多种药理学，包括CDK9， Aurka，EGFR，BRAF和RAF1。在此提案中，我们研究了这些提案的机制和重要性 使用遗传分析和体内靶标参与的其他推定的促靶激酶和抗目标激酶。目标 是通过将化学生物学与遗传学相结合，识别介导KRAS变异MCRC的激酶网络， 然后，通过基于结构的药物设计得出最能攻击这些网络的抑制剂。我们去过 以前采用类似的方法成功，但在不太复杂的肿瘤模型中（Dar等，Nature，2012年； Sonoshita等人，自然化学。 Bio。，2018）;在这里，我们试图将平台扩展到更普遍的疾病 目的是通过创建新的，高度差异化和改进的药物来直接影响MCRC。