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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要转移性结直肠癌 (mCRC) 是美国癌症相关死亡的第二大原因目前，小分子激酶每年导致全球近 50 万人死亡。抑制剂 (KI) 瑞戈非尼是治疗无法用药物治疗的转移性 CRC 的主要二线疗法然而，瑞戈非尼通常只能提供适度的改善。生存期（通常为几个月），并且通常以显着副作用为代价。包括在肿瘤细胞内发挥作用的激酶以及非自主作用的激酶，有超过 500 个可能的靶点；在人类激酶组中，这种化合物起作用的确切机制仍然存在争议，并且不存在众所周知，这是一个艰巨的挑战；如果没有可验证的目标或机制，就不存在明确的道路。指导 mCRC 改良疗法的开发。在这里，我们提出了一种药物开发的替代方法，重点关注激酶网络具体来说，我们将采用多学科方法来定义激酶。在使用果蝇的 KRAS 变异 CRC 中，有利于抑制（“前靶标”）或避免（“反靶标”）。和哺乳动物模型，我们将鉴定出激酶，当其减少时，会改变瑞戈非尼的功效，我们还将进行广泛的结构-活性关系分析，评估如何进行。最后，我们对已确定的先导化合物进行修改会影响功效和治疗指数的变化。将利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在最后一步中，我们生成新的类似物以选择性地消除假定的。抗靶标活性，同时维持或增加针对其他有益靶标的抑制活性。我们利用我们的化学遗传平台鉴定了一种有前途的先导化合物 APS5-86-2，在多种转移性结直肠癌模型（包括人类患者）中表现出相对于瑞戈非尼的显着活性比较分析表明，APS5-86-2 的活性相对于 PDX 有所提高。瑞戈非尼源自多种 RTK 和关键癌症驱动因素的独特多药理学，包括 CDK9、 AURKA、EGFR、BRAF 和 RAF1 在本提案中，我们研究了它们的机制和重要性。使用遗传分析和体内靶点参与的其他推定的亲靶点和抗靶点激酶。是通过结合化学生物学和遗传学来识别介导 KRAS 变异 mCRC 的激酶网络，然后通过基于结构的药物设计衍生出最能攻击这些网络的抑制剂。以前使用类似的方法取得了成功，但在不太复杂的肿瘤模型中（Dar 等人，Nature，2012； Sonoshita 等人，Nature Chem.，2018）；我们寻求将我们的平台扩展到更普遍的疾病目标是通过创造新的、高度差异化和改进的药物来直接影响转移性结直肠癌。