Novel inhibitor for oncogenic RAS for lung cancer

肺癌致癌 RAS 的新型抑制剂

基本信息

  • 批准号:
    10408381
  • 负责人:
  • 金额:
    $ 39.46万
  • 依托单位:
  • 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 2026-06-30
  • 项目状态:
    未结题

项目摘要

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基因的功能获得性突变通常由烟草源致癌物引起。组成性激活 RAS(一种GT酶)刺激下游激酶级联反应,激活编码蛋白质的基因 对于肿瘤发生的多个方面(包括肿瘤细胞增殖、存活和转移)至关重要。 由于KRAS在肺癌的早期阶段发生突变,并且是肿瘤促进的主要驱动因素, 作为一种直接作用的、可逆的小分子活化RAS抑制剂, 癌症化学预防或治疗患有早期疾病的个体。不幸的是,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缺 适合于小分子结合。然而,正在进行的两种共价抑制剂的临床试验, 罕见的KRAS G12 C突变已经验证了这种方法,可以扩展到抑制剂有效, 在肺癌患者和其他RAS驱动的恶性肿瘤中普遍存在更广泛的RAS突变。一 一个长期运行的药物化学计划,负责合成一个重点图书馆的茚和 在基于细胞的测定中筛选RAS选择性导致发现了一类新的RAS抑制剂。 MCI-062在广泛的化学优化和迭代靶向靶向药物筛选后作为先导化合物出现。 筛选用MCI-062体外处理携带突变型RAS的肺癌细胞抑制生长,IC 50 值低至2 nM,而人正常气道上皮细胞或具有低水平活化RAS的肿瘤细胞, 本质上是麻木不仁的。MCI-062是有效的,无论RAS同工酶或突变密码子, 在临床试验中比KRAS的共价突变特异性抑制剂明显更有效。多行 证据表明MCI-062通过直接与RAS相互作用抑制GTP结合来抑制肿瘤细胞生长, 阻断RAS-效应物相互作用,抑制RAF/MAPK和PI 3 K/AKT信号传导,导致选择性 RAS突变肿瘤细胞的凋亡。作为概念验证,MCI-062和原型前药MCI-316抑制了 尽管需要进一步的化学优化以开发适合于体内肿瘤生长的口服制剂, 临床前开发。一种新的前药MCI-1004最近从正在进行的合成努力中出现, 具有吸引人的药物样特性,值得进行体内测试。我们的目标是:1)进一步了解MCI- 062选择性抑制具有活化RAS的肺癌细胞的生长; 2)合成新的类似物, 通过口服递送改善抗肿瘤活性的前药,并将它们与MCI-1004进行基准比较,以及3)评估 MCI-1004和第二前药先导物在肺癌化学预防小鼠模型中的抗肿瘤活性 以及与临床相关的治疗方法。这些目标的结构是平行进行的,目的是 转化为优化和选择候选药物以实现IND安全性的目标 评估,并获得生物标志物的机械原理,这将有助于选择未来的患者队列 临床试验

项目成果

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Gary A Piazza其他文献

Gary A Piazza的其他文献

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{{ truncateString('Gary A Piazza', 18)}}的其他基金

Novel inhibitor for oncogenic RAS for lung cancer
肺癌致癌 RAS 的新型抑制剂
  • 批准号:
    10312820
  • 财政年份:
    2021
  • 资助金额:
    $ 39.46万
  • 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
  • 批准号:
    10456469
  • 财政年份:
    2021
  • 资助金额:
    $ 39.46万
  • 项目类别:
Novel inhibitor for oncogenic RAS for lung cancer
肺癌致癌 RAS 的新型抑制剂
  • 批准号:
    10664823
  • 财政年份:
    2021
  • 资助金额:
    $ 39.46万
  • 项目类别:
Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment
利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症
  • 批准号:
    10113565
  • 财政年份:
    2020
  • 资助金额:
    $ 39.46万
  • 项目类别:
Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment
利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症
  • 批准号:
    9917342
  • 财政年份:
    2020
  • 资助金额:
    $ 39.46万
  • 项目类别:
Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment
利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症
  • 批准号:
    10360574
  • 财政年份:
    2020
  • 资助金额:
    $ 39.46万
  • 项目类别:
Exploiting the immunomodulatory effects of sulindac and novel non-COX inhibitory derivatives for cancer treatment
利用舒林酸和新型非 COX 抑制衍生物的免疫调节作用来治疗癌症
  • 批准号:
    10594951
  • 财政年份:
    2020
  • 资助金额:
    $ 39.46万
  • 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
  • 批准号:
    9198369
  • 财政年份:
    2016
  • 资助金额:
    $ 39.46万
  • 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
  • 批准号:
    9316610
  • 财政年份:
    2016
  • 资助金额:
    $ 39.46万
  • 项目类别:
Phosphodiesterase 10A, a novel target for lung cancer chemoprevention
磷酸二酯酶10A,肺癌化学预防的新靶点
  • 批准号:
    9904554
  • 财政年份:
    2016
  • 资助金额:
    $ 39.46万
  • 项目类别:

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