Development of covalent PIP4K2 inhibitors for the treatment of p53 deficient lung tumors

开发共价 PIP4K2 抑制剂用于治疗 p53 缺陷型肺部肿瘤

基本信息

批准号：
8942703
负责人：
NATHANAEL Schiander GRAY
金额：
$ 54.09万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-07 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8942703
关键词：
A549 Accounting Address Biochemical Biochemistry Cancer cell line Cancerous Cell Line Cellular Assay Cessation of life Clinical Clinical Research Clinical Trials Dana-Farber Cancer Institute Development Disease Drug Kinetics Drug Targeting Engineering Environmental Exposure Event Genes Genetic Engineering Germ Lines Goals Gray unit of radiation dose Growth Hour KRAS2 gene Lead Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Mus Mutate Mutation Oral Administration Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phosphotransferases Pre-Clinical Model Premalignant Cell Property Proteins Research Research Proposals Resistance Resolution Roentgen Rays Series Signal Transduction Smoking Structure TP53 gene Testing Translational Research Tumor Suppressor Genes Work Xenograft Model Xenograft procedure analog base cancer cell cell growth cell killing design in vivo inhibitor/antagonist medical schools mutant phosphatidylinositol 5-phosphate prototype public health relevance research clinical testing small molecule structural biology therapeutic target tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Loss or mutations in the tumor suppressor gene TP53 (encoding p53) is one of the most frequent events in cancer. Clinical and functional studies have unequivocally validated the functional importance of the loss of p53 in cancer but unfortunately there are no small molecule approaches to address this challenge. Our labs have recently demonstrated that the kinase activity of type 2 phosphatidylinositol-5-phosphate 4-kinase A and B (PIP4K2A and B) encoded by PIP4K2A and PIP4K2B genes are crucial for the growth of cancers that harbor TP53 deletions. Specifically we have demonstrated that germ line deletion of PIP4K2A and PIP4K2B in mice suppresses tumor formation in the context of TP53 deletion and that prototype inhibitors selectively kill cells harboring TP53 deletions. The goal of this proposal is to develop the first covalent PIP4K2 inhibitors with the requisite potency, selectivity and pharmacological properties to interrogate the potential of PIP4K2 as a therapeutic target in lung cancer and other diseases characterized by loss of p53 function and high level of PIP4K2s. We have developed a prototype covalent PIP4K2 inhibitor, THZ-2-72-1, which irreversibly targets PIP4K2 and selectively inhibits the proliferation of p53 deficient lung cancer cell lines. We will use a focused medicinal chemistry approach informed by modeling and co-crystal structures to develop optimized inhibitors that can be tested using xenograft, genetically engineered and primagraft models for their ability to inhibit TP53-deficient tumor growth. These studies will serve to pharmacologically validate PIP4K2 as a new target and will provide prototype drugs that can be further optimized for eventual clinical testing.

描述（由适用提供）：肿瘤抑制基因TP53（编码p53）中的损失或突变是癌症中最常见的事件之一。临床和功能研究已经明确验证了癌症p53损失的功能重要性，但不幸的是，没有针对这一挑战的小分子方法。我们的实验室最近表明，由PIP4K2A和PIP4K2B基因编码的2型磷脂酰肌醇-5-磷酸4-激酶A和B（PIP4K2A和B）的激酶活性对于携带Tp53删除的癌症的生长至关重要。具体而言，我们已经证明了小鼠中PIP4K2A和PIP4K2B的生殖系缺失在TP53缺失的背景下抑制肿瘤的形成，并且原型抑制剂有选择地杀死具有TP53缺失的细胞。目标该建议是开发出首个具有必要效力，选择性和药物特性的共价PIP4K2抑制剂，以询问PIP4K2作为肺癌中的治疗靶标的潜力以及其他疾病，其特征是p53功能丧失和PIP4K2的高水平。我们已经开发了共价PIP4K2抑制剂THZ-2-72-1的原型原型，该抑制剂不可逆地靶向PIP4K2，并有选择地抑制p53不足的肺癌细胞系的增殖。我们将使用通过建模和共晶结构进行的专注医学化学方法来开发优化的抑制剂，这些抑制剂可以使用Xenographing，一般设计的和Primagraft模型进行测试，以抑制TP53缺陷型肿瘤的生长。这些研究将用于药物验证PIP4K2作为新靶标，并将提供可以进一步优化最终临床测试的原型药物。