Novel TYRO3 inhibitors for treatment of cancer

用于治疗癌症的新型 TYRO3 抑制剂

基本信息

  • 批准号:
    10381542
  • 负责人:
  • 金额:
    $ 31.66万
  • 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:
    2021-04-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. All three family members are aberrantly expressed in cancer cells, where they function to promote cell survival, mediate resistance to a variety of cytotoxic chemotherapies and molecularly-targeted agents and have additional roles in macrophages and other innate immune cells where they function to suppress anti-tumor immunity, leading to enhanced tumor growth and metastasis. These and other data implicate the TAM kinases as potential therapeutic targets in a wide variety of human tumors. Moreover, because of the oncogenic roles for TAM kinases in both tumor and immune cells, inhibitors are expected to provide anti-tumor action mediated by both direct tumor cell killing and modulation of the innate immune response. While the TAM kinases have overlapping functions, they also play unique roles in some contexts. Specifically, our preliminary data suggest that suppression of anti-tumor immunity is particularly dependent on TYRO3. Here, we propose to utilize a well-established and productive team of researchers along with computational-aided drug design and enzymatic, cell-based and pharmacodynamic assays to develop novel, potent, and selective TYRO3 inhibitors and validate their biochemical and functional activities in TYRO3- dependent tumor xenograft models and immune-competent syngeneic cancer models. TYRO3 can localize to the nucleus and inhibition of nuclear localization induced apoptosis in colon cancer cells, suggesting non- canonical oncogenic functions for TYRO3 which might not be effectively targeted by kinase inhibition alone. Thus, both traditional small molecule kinase inhibitors and proteolysis-targeting chimeric (PROTAC) degraders that selectively target TYRO3 for ubiquitination and degradation will be developed and compared. At the completion of this work, we expect to deliver a TYRO3-selective inhibitor suitable for advancement to GLP toxicity studies in multiple species, sufficient preclinical validation studies to support an IND application describing this compound, and a viable method for large-scale synthesis of the compound.
TYRO3是TAM (TYRO3, AXL, MERTK)受体酪氨酸激酶家族的一员。所有三个

项目成果

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DOUGLAS K GRAHAM其他文献

DOUGLAS K GRAHAM的其他文献

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{{ truncateString('DOUGLAS K GRAHAM', 18)}}的其他基金

Novel TYRO3 inhibitors for treatment of cancer
用于治疗癌症的新型 TYRO3 抑制剂
  • 批准号:
    10182743
  • 财政年份:
    2021
  • 资助金额:
    $ 31.66万
  • 项目类别:
Novel TYRO3 inhibitors for treatment of cancer
用于治疗癌症的新型 TYRO3 抑制剂
  • 批准号:
    10582629
  • 财政年份:
    2021
  • 资助金额:
    $ 31.66万
  • 项目类别:
MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunity
MERTK/AXL双重抑制剂通过靶向肿瘤细胞并激活抗肿瘤免疫为癌症提供新的治疗方法
  • 批准号:
    10373031
  • 财政年份:
    2020
  • 资助金额:
    $ 31.66万
  • 项目类别:
MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunity
MERTK/AXL双重抑制剂通过靶向肿瘤细胞并激活抗肿瘤免疫为癌症提供新的治疗方法
  • 批准号:
    10589107
  • 财政年份:
    2020
  • 资助金额:
    $ 31.66万
  • 项目类别:
Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC
项目 2:靶向 MERTK 改善 EGFR 突变 NSCLC 的预后
  • 批准号:
    10685418
  • 财政年份:
    2019
  • 资助金额:
    $ 31.66万
  • 项目类别:
Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC
项目 2:靶向 MERTK 改善 EGFR 突变 NSCLC 的预后
  • 批准号:
    10210199
  • 财政年份:
    2019
  • 资助金额:
    $ 31.66万
  • 项目类别:
Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC
项目 2:靶向 MERTK 改善 EGFR 突变 NSCLC 的预后
  • 批准号:
    10459441
  • 财政年份:
    2019
  • 资助金额:
    $ 31.66万
  • 项目类别:
Novel Biologically Targeted Therapy Against the Mer and Axl Receptor Tyrosine Kin
针对 Mer 和 Axl 受体酪氨酸激酶的新型生物靶向疗法
  • 批准号:
    8118019
  • 财政年份:
    2010
  • 资助金额:
    $ 31.66万
  • 项目类别:
Novel Biologically Targeted Therapy Against the Mer and Axl Receptor Tyrosine Kin
针对 Mer 和 Axl 受体酪氨酸激酶的新型生物靶向疗法
  • 批准号:
    8267692
  • 财政年份:
    2010
  • 资助金额:
    $ 31.66万
  • 项目类别:
Novel Biologically Targeted Therapy Against the Mer and Axl Receptor Tyrosine Kin
针对 Mer 和 Axl 受体酪氨酸激酶的新型生物靶向疗法
  • 批准号:
    7992763
  • 财政年份:
    2010
  • 资助金额:
    $ 31.66万
  • 项目类别:

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