Development of First-in-Class RIPK1 Degraders to Improve Cancer Immunotherapies
开发一流的 RIPK1 降解剂以改善癌症免疫疗法
基本信息
- 批准号:10390589
- 负责人:
- 金额:$ 65.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-07 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAdvanced Malignant NeoplasmAntigensApoptosisBiological AssayBiological MarkersBiologyCancer PatientCancer cell lineCanis familiarisCell SurvivalCellsChemicalsClinicalComplexDevelopmentDoseDrug ExposureFutureGenetic studyHalf-LifeHumanImmuneImmune systemImmunocompetentImmunophenotypingImmunotherapyIndividualInterferonsInterventionInvestigationKnock-outLigandsModelingMonkeysMonoclonal AntibodiesMusMutationOralOutcomePathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPharmacology and ToxicologyPhenocopyPhenotypePhosphotransferasesPlasmaPre-Clinical ModelPropertyProtacProtein KinaseProteinsProteomeProteomicsRIPK1 geneRattusResearchScaffolding ProteinSignal TransductionSpecificitySymptomsT-LymphocyteTNF geneTechnologyTestingTherapeuticTherapeutic AgentsToll-like receptorsTransgenic MiceTransgenic OrganismsTumor ImmunityVariantWorkanti-PD-1basecancer cellcancer immunotherapycancer therapyclinical translationcongenital immunodeficiencyefficacy evaluationgut inflammationhumanized mouseimmune checkpoint blockadeimprovedin vivoinhibitorinnate immune pathwaysinnovationloss of functionmelanomamouse modelmultiple omicsnovel therapeuticspatient responsepatient stratificationpotential biomarkerrecruitresponsespecies differencesuccesstranscriptometriple-negative invasive breast carcinomatumortumor growthtumor microenvironment
项目摘要
Abstract
Cancer immunotherapies have achieved unprecedented clinical responses and are revolutionizing cancer
treatments. Despite of the tremendous success of cancer immunotherapies, it remains unclear why only a subset
of individuals responds to treatment and how to turn non-responders to become responsive. Receptor-interacting
protein kinase 1 (RIPK1) regulates cell fate and proinflammatory signaling downstream of multiple innate immune
pathways, including those initiated by tumor necrosis factor-α (TNF-α), toll-like receptor ligands, and interferons.
In TNF-α signaling, the kinase activity of RIPK1 is required for inducing apoptosis and necroptosis. RIPK1 also
serves as a kinase-independent scaffolding protein to recruit the NF-κB activation complex, leading to activation
of the NF-κB pathway and cell survival. Interestingly, mice with a kinase-dead Ripk1 mutation (mimicking
inhibitors) and with Ripk1 knockout (mimicking degraders) showed completely different phenotypes. Recently,
our work, along with two other independent studies, showed that knockout of RIPK1 in cancer cells
significantly sensitized tumors to anti-PD1, leading to favorable changes in the tumor microenvironment.
Homozygous loss-of-function RIPK1 mutations are well tolerated in humans. Patients with complete loss of
RIPK1 protein only showed symptoms confined to the immune system with primary immunodeficiency and/or
intestinal inflammation, suggesting that pharmacological RIPK1 degradation can be potentially safe and tolerable,
especially with transient intervention in clinical settings. Leveraging the Proteolysis targeting chimera (PROTAC)
technology, we developed a first-in-class RIPK1 degrader LD4172. In our preliminary study, we showed that
LD4172 potently degrades RIPK1 protein in a panel of human cancer cell lines and inhibits NF-κB activities. The
degradation specificity of LD4172 was confirmed with proteomics profiling. In a mouse melanoma
immunocompetent model, LD4172 significantly synergized with anti-PD1. In this project, we will continue our
medicinal chemistry campaign to develop an orally available RIPK1 degrader and test its efficacy in a panel of
preclinical models with different immune subtypes. Successful completion of this project will lead to the
development of not only a chemical probe to interrogate RIPK1 related biology but also a highly promising
therapeutic agent to advance cancer immunotherapies. We strive to use diverse preclinical models to test the
RIPK1 degrader to identify biomarkers, which is very important to identify responsive patients in future clinical
translations.
摘要
癌症免疫疗法已经取得了前所未有的临床反应,并正在彻底改变癌症
治疗。尽管癌症免疫疗法取得了巨大的成功,但仍不清楚为什么只有一个子集
对治疗有反应的个体以及如何将无反应者转变为有反应者。受体相互作用
蛋白激酶1(RIPK 1)调节细胞命运和多种先天性免疫下游的促炎信号传导
途径,包括由肿瘤坏死因子-α(TNF-α)、toll样受体配体和干扰素启动的途径。
在TNF-α信号传导中,RIPK 1的激酶活性是诱导细胞凋亡和坏死性凋亡所必需的。RIPK1
作为激酶非依赖性支架蛋白,募集NF-κB活化复合物,导致活化
NF-κB通路和细胞存活。有趣的是,具有激酶死亡的Ripk 1突变的小鼠(模拟
抑制剂)和Ripk 1敲除(模拟降解剂)显示出完全不同的表型。最近,
我们的工作,沿着另外两项独立的研究,表明在癌细胞中敲除RIPK 1,
显著地使肿瘤对抗PD 1敏感,导致肿瘤微环境的有利变化。
RIPK 1纯合子功能丧失突变在人类中耐受良好。完全丧失的患者
RIPK 1蛋白仅表现出局限于免疫系统的原发性免疫缺陷和/或
肠道炎症,表明药理学RIPK 1降解可能是安全和耐受的,
特别是在临床环境中的瞬时干预。利用蛋白水解靶向嵌合体(PROTAC)
技术,我们开发了一流的RIPK 1降能器LD 4172。在我们的初步研究中,我们表明,
LD 4172可有效降解一组人癌细胞系中的RIPK 1蛋白并抑制NF-κB活性。的
LD 4172的降解特异性用蛋白质组学分析证实。在一只老鼠的黑色素瘤中
在免疫活性模型中,LD 4172与抗PD 1显著协同。在这个项目中,我们将继续我们的
药物化学活动,以开发口服RIPK 1降解剂,并在一组
具有不同免疫亚型的临床前模型。该项目的成功完成将导致
不仅开发了一种询问RIPK 1相关生物学的化学探针,
用于促进癌症免疫疗法的治疗剂。我们努力使用不同的临床前模型来测试
RIPK 1降解剂用于识别生物标志物,这对于在未来的临床中识别有反应的患者非常重要
翻译.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jin Wang其他文献
Jin Wang的其他文献
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{{ truncateString('Jin Wang', 18)}}的其他基金
Mathematical Modeling and Scientific Computing for Infectious Disease Research
传染病研究的数学建模和科学计算
- 批准号:
10793008 - 财政年份:2023
- 资助金额:
$ 65.28万 - 项目类别:
Development of First-in-Class RIPK1 Degraders to Improve Cancer Immunotherapies
开发一流的 RIPK1 降解剂以改善癌症免疫疗法
- 批准号:
10661495 - 财政年份:2022
- 资助金额:
$ 65.28万 - 项目类别:
Development of First-in-Class RIPK1 Degraders to Improve Cancer Immunotherapies
开发一流的 RIPK1 降解剂以改善癌症免疫疗法
- 批准号:
10746264 - 财政年份:2022
- 资助金额:
$ 65.28万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10503835 - 财政年份:2020
- 资助金额:
$ 65.28万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10802956 - 财政年份:2020
- 资助金额:
$ 65.28万 - 项目类别:
Reversible Covalent BTK Degraders as the Next Generation Targeted Therapy to Treat B-cell Malignancies
可逆共价 BTK 降解剂作为治疗 B 细胞恶性肿瘤的下一代靶向疗法
- 批准号:
10737768 - 财政年份:2020
- 资助金额:
$ 65.28万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10412114 - 财政年份:2020
- 资助金额:
$ 65.28万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10663178 - 财政年份:2020
- 资助金额:
$ 65.28万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10032662 - 财政年份:2020
- 资助金额:
$ 65.28万 - 项目类别:
Developing Novel Soluble Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的新型可溶性环氧化物水解酶抑制剂
- 批准号:
10261446 - 财政年份:2020
- 资助金额:
$ 65.28万 - 项目类别: