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：
Jin Wang
金额：
$ 65.28万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
https://reporter.nih.gov/project-details/10390589
关键词：
Accounting Advanced Malignant Neoplasm Antigens Apoptosis Biological Assay Biological Markers Biology Cancer Patient Cancer cell line Canis familiaris Cell Survival Cells Chemicals Clinical Complex Development Dose Drug Exposure Future Genetic study Half-Life Human Immune Immune system Immunocompetent Immunophenotyping Immunotherapy Individual Interferons Intervention Investigation Knock-out Ligands Modeling Monkeys Monoclonal Antibodies Mus Mutation Oral Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phenocopy Phenotype Phosphotransferases Plasma Pre-Clinical Model Property Protac Protein Kinase Proteins Proteome Proteomics RIPK1 gene Rattus Research Scaffolding Protein Signal Transduction Specificity Symptoms T-Lymphocyte TNF gene Technology Testing Therapeutic Therapeutic Agents Toll-like receptors Transgenic Mice Transgenic Organisms Tumor Immunity Variant Work anti-PD-1 base cancer cell cancer immunotherapy cancer therapy clinical translation congenital immunodeficiency efficacy evaluation gut inflammation humanized mouse immune checkpoint blockade improved in vivo inhibitor innate immune pathways innovation loss of function melanoma mouse model multiple omics novel therapeutics patient response patient stratification potential biomarker recruit response species difference success transcriptome triple-negative invasive breast carcinoma tumor tumor growth tumor 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.

抽象的癌症免疫疗法取得了前所未有的临床反应，正在彻底改变癌症尽管癌症免疫疗法取得了巨大成功，但仍不清楚为什么只有一小部分。个体对治疗有反应以及如何使无反应者变得有反应。蛋白激酶 1 (RIPK1) 调节多种先天免疫下游的细胞命运和促炎信号传导途径，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，RIPK1 的激酶活性也是诱导细胞凋亡和坏死性凋亡所必需的。作为激酶独立的支架蛋白来募集 NF-κB 激活复合物，从而导致激活 NF-κB 通路和细胞存活的关系。最近，Ripk1 敲除（模仿降解剂）表现出完全不同的表型。我们的工作以及另外两项独立研究表明，在癌细胞中敲除 RIPK1 使肿瘤对抗PD1显着敏感，导致肿瘤微环境发生有利的变化。人类完全丧失功能的纯合子 RIPK1 突变具有良好的耐受性。 RIPK1 蛋白仅表现出仅限于原发性免疫缺陷和/或免疫系统的症状肠道炎症，表明药理学 RIPK1 降解可能是安全且可耐受的，尤其是在临床环境中利用蛋白水解靶向嵌合体 (PROTAC) 进行短暂干预。技术，我们开发了一流的 RIPK1 降解剂 LD4172 在我们的初步研究中，我们表明： LD4172 能有效降解一组人类癌细胞系中的 RIPK1 蛋白并抑制 NF-κB 活性。 LD4172 的降解特异性在小鼠黑色素瘤中得到了蛋白质组学分析的证实。在免疫活性模型中，LD4172 与抗 PD1 具有显着的协同作用，在这个项目中，我们将继续我们的研究。药物化学运动旨在开发一种口服 RIPK1 降解剂并在一组药物中测试其功效不同免疫亚型的临床前模型的成功完成将导致不仅开发了一种用于研究 RIPK1 相关生物学的化学探针，而且还开发了一种非常有前途的我们努力使用多种临床前模型来测试癌症免疫疗法。 RIPK1降解剂识别生物标志物，这对于未来临床中识别有反应的患者非常重要翻译。