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:
    10312820
  • 负责人:
  • 金额:
    $ 39.06万
  • 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信号的异常激活是导致肺癌的主要驱动因素

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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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

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:
    $ 39.06万
  • 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:
    $ 39.06万
  • 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:
    10408381
  • 财政年份:
    2021
  • 资助金额:
    $ 39.06万
  • 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:
    $ 39.06万
  • 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:
    $ 39.06万
  • 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:
    $ 39.06万
  • 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:
    $ 39.06万
  • 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:
    $ 39.06万
  • 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:
    $ 39.06万
  • 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:
    $ 39.06万
  • 项目类别:

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