Novel inhibitor for oncogenic RAS for lung cancer

肺癌致癌 RAS 的新型抑制剂

• 批准号: 10312820
• 负责人: Gary A Piazza
• 金额: $ 39.06万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10312820
• 关键词: Affect; Amides; Antineoplastic Agents; Apoptosis; Benchmarking; Binding; Biochemical; Biological Assay; Biological Availability; Biological Markers; Cancer Cell Growth; Cancer Patient; Carbamates; Carcinogens; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cell physiology; Cells; Chemicals; Chemoprevention; Clinic; Clinical Chemoprevention; Clinical Trials; Code; Codon Nucleotides; Derivation procedure; Development; Disease; Drug Kinetics; Early treatment; Epithelial Cells; Formulation; Future; GTP Binding; Genes; Genetic Engineering; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Histologic; Human; Hydroxyl Radical; In Vitro; Indenes; Individual; Isoenzymes; KRAS2 gene; Lead; Libraries; Lung; Lung Neoplasms; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Medical; Metabolic; Modeling; Molecular Conformation; Mutate; Mutation; Neoplasm Metastasis; Normal tissue morphology; Nucleotides; Oncogenic; Oncology; Oral; Oral Administration; PI3K/AKT; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenols; Phosphoproteins; Phosphotransferases; Plant Roots; Prodrugs; Property; Proteins; Proto-Oncogene Proteins c-akt; RAS genes; RAS inhibition; Ras Inhibitor; Recombinants; Research; Resistance; Risk; Running; Series; Signal Transduction; Site; Solubility; Structure; Synthesis Chemistry; Testing; Therapeutic; Tobacco; Tumor Cell Line; Tumor Promotion; Tumor Tissue; Water; Xenograft procedure; airway epithelium; analog; base; cancer cell; cancer chemoprevention; cancer therapy; cell growth; cigarette smoke; clinical candidate; cohort; design; drug development; efficacy evaluation; experimental study; improved; in vitro Model; in vivo; in vivo evaluation; inhibitor; insight; lung cancer cell; lung tumorigenesis; mouse model; mutant; neoplastic cell; novel; patient derived xenograft model; potential biomarker; preclinical development; programs; prototype; ras Proteins; safety assessment; screening; small molecule; small molecule inhibitor; translational potential; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis

Project Summary/Abstract: Aberrant activation of RAS signaling is a major driver of lung cancer resulting from gain-in-function mutations in RAS genes often caused by tobacco-derived carcinogens. Constitutive activation of RAS, a GTPase, stimulates a cascade of downstream kinases to activate genes encoding for proteins essential for multiple aspects of tumorigenesis, including tumor cell proliferation, survival, and metastasis. Because KRAS is mutated during early stages of lung cancer and a major driver of tumor promotion and progression, a direct-acting, reversible, small molecule inhibitor of activated RAS holds great potential for lung cancer chemoprevention or the treatment of individuals with early stage disease. Unfortunately, previous attempts to develop RAS inhibitors were unsuccessful, in part, because of the scarcity of sites on the protein amenable to small-molecule binding. However, ongoing clinical trials of two covalent inhibitors of the relatively rare KRAS G12C mutation have validated this approach that can be expanded to inhibitors effective for a much broader spectrum of RAS mutations prevalent in lung cancer patients and other RAS-driven malignancies. A long-running medicinal chemistry program undertaking the synthesis of a focused library of indenes and screening in a cell-based assay for RAS selectivity resulted in the discovery of a novel class of RAS inhibitors. MCI-062 emerged as a lead compound following extensive chemical optimization and iterative target-directed screening. In vitro treatment of lung cancer cells harboring mutant RAS with MCI-062 inhibited growth with IC50 values as low as 2 nM, while human normal airway epithelial cells or tumor cells with low levels of activated RAS were essentially insensitive. MCI-062 was effective regardless of the RAS isozyme or mutational codon and appreciably more potent than covalent mutant-specific inhibitors of KRAS in clinical trials. Multiple lines of evidence indicate that MCI-062 inhibits tumor cell growth by directly interacting with RAS to inhibit GTP binding, blocking RAS-effector interaction, suppressing RAF/MAPK and PI3K/AKT signaling, resulting in selective apoptosis of RAS mutant tumor cells. As proof-of-concept, MCI-062 and a prototype prodrug, MCI-316, inhibited tumor growth in vivo, although further chemical optimization is needed to develop an oral formulation suitable for preclinical development. A new prodrug, MCI-1004 recently emerged from ongoing synthetic efforts with attractive drug-like properties that merit in vivo testing. We propose aims to: 1) gain further insight into how MCI- 062 selectively inhibits the growth of lung cancer cells with activated RAS; 2) synthesize new analogs and prodrugs to improve antitumor activity by oral delivery and benchmark them against MCI-1004, and 3) evaluate antineoplastic activity of MCI-1004 and a second prodrug lead in mouse models of lung cancer chemoprevention and treatment that are relevant to the clinic. The aims are structured to be conducted in parallel and designed to be translational with the goals of optimizing and selecting a drug development candidate for IND-enabling safety assessment and to gain a mechanistic rationale for biomarkers that will aid in selecting patient cohorts for future clinical trials.

项目摘要/摘要：RAS信号的异常激活是肺癌的主要驱动因素 RAS基因的功能增益突变通常是由烟草衍生的致癌物引起的。本构活化 RAS是一种GTP酶，它能刺激下游一系列的激酶，从而激活编码蛋白质的基因 对肿瘤发生的多个方面至关重要，包括肿瘤细胞的增殖、存活和转移。 因为KRAS在肺癌的早期阶段发生突变，是肿瘤促进和 PROCESS是一种直接作用的、可逆的、激活的RAS的小分子抑制剂，对肺具有巨大的潜力 癌症的化学预防或早期疾病的治疗。不幸的是，之前 开发RAS抑制剂的尝试没有成功，部分原因是蛋白质上的位点稀少 易受小分子结合。然而，正在进行的两种相对分子水平的共价抑制剂的临床试验 罕见的KRAS G12C突变验证了这种方法，这种方法可以扩展为有效的抑制剂 在肺癌患者和其他RAS驱动的恶性肿瘤中普遍存在的更广泛的RAS突变。一个 长期运行的药物化学计划，负责合成一个重点关注的吲哚和 在基于细胞的RAS选择性试验中的筛选导致了一类新的RAS抑制剂的发现。 经过广泛的化学优化和反复的目标导向，MCI-062成为了一种先导化合物 放映。MCI-062对携带突变型RAS基因的肺癌细胞生长抑制作用的IC50 值低至2 NM，而人正常呼吸道上皮细胞或低水平激活的RAS的肿瘤细胞 本质上是麻木不仁的。无论RAS同工酶或突变密码子如何，MCI-062都是有效的 在临床试验中，KRAS的共价突变特异性抑制剂的效力明显高于共价突变的KRAS抑制剂。多行 有证据表明，MCI-062通过直接与RAS相互作用抑制GTP结合，从而抑制肿瘤细胞的生长。 阻断RAS-效应器相互作用，抑制RAF/MAPK和PI3K/AKT信号，导致选择性 RAS突变型肿瘤细胞的凋亡。作为概念验证，MCI-062和原型前体药物MCI-316被抑制 体内肿瘤生长，尽管需要进一步的化学优化来开发适合于 临床前发展。一种新的前药MCI-1004最近从正在进行的合成努力中出现 有吸引力的药物性质，值得在体内测试。我们提出的目标是：1)进一步了解MCI如何- 062用活化的RAS选择性抑制肺癌细胞的生长；2)合成新的类似物和 通过口服提高抗肿瘤活性的前药，并以MCI-1004为基准，以及3)评估 MCI-1004和第二前药铅在小鼠肺癌化学预防模型中的抗肿瘤活性 以及与临床相关的治疗。这些目标的结构是并行进行的，旨在 翻译，目标是优化和选择实现IND安全性的候选药物开发 评估并获得生物标记物的机械原理，以帮助选择未来的患者队列 临床试验。