Selective RET Kinase and Its Mutant Inhibitors for the Treatment of Medullary Thyroid Cancer

选择性RET激酶及其突变抑制剂治疗甲状腺髓样癌

基本信息

批准号：
9547328
负责人：
Hong-Yu Li
金额：
$ 28.5万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
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：
2015-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9547328
关键词：
Active Sites Animals Automobile Driving Binding Biochemical Biological Assay Biological Availability Biological Markers Blood Vessels Cancer cell line Cause of Death Cell Proliferation Cells Chemicals Chromosomal Rearrangement Clinical Complex Computer Simulation Crystallization Data Analyses Disease Dose Dose-Limiting Endocrine Extracellular Domain Fibroblasts Gatekeeping Generations Genes Genetic Goals Hemorrhage Human Hypertension In Vitro KDR gene Lead Malignant Neoplasms Medical Metabolic Modification Mus Mutation Neoplasms Oncogenes Oral Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phospho-Specific Antibodies Phosphotransferases Point Mutation Process Progression-Free Survivals Proteins RET inhibition Rattus Research Research Proposals Roentgen Rays Series Signal Pathway Signal Transduction Site Specificity Structure Structure of thyroid parafollicular cell Syndrome Technology Therapeutic Therapeutic Agents Thromboembolism Thyroid Gland Time Toxic effect Transfection United States VEGFR inhibition Xenograft Model antiangiogenesis therapy assay development base benzimidazole cancer cell cancer survival cell growth clinical candidate combat design effective therapy functional group gain of function improved in vitro Assay in vitro activity in vivo inhibitor/antagonist kinase inhibitor medullary thyroid carcinoma mutant next generation novel novel therapeutics placebo group preclinical study prevent public health relevance receptor screening tumor growth tumor xenograft virtual

项目摘要

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in United States and new therapeutics are desperately needed to combat the disease. In 1985, the RET (RE-arranged during Transfection) gene was identified as a novel oncogene activated through chromosomal rearrangement. Since then, RET has been identified as a driving oncogene in several cancers, especially for medullary thyroid cancer (MTC). Due to the challenges of identifying a selective RET inhibitor, a treatment for MTC is still an unmet medical need. In an effort to develop a RET kinase inhibitor, a picomolar RET/VEGFR2 clinical candidate has been developed and is currently in preclinical studies. However, the inhibition of VEGFR2 is associated with vascular on-target dose-limiting toxicities, including hypertension in patients for most VEGFR2 inhibitor drugs. We wish to further develop an inhibitor by removing VEGFR2 activity and improving overall selectivity in the kinome, thereby achieving maximal/or complete inhibition of the RET-signaling pathway in patients. We will utilize validated computational models of RET and VEGFR2, fragment-based screening, and potential X-ray crystal structural information to develop a clinical candidate with >30 times RET selectivity over VEGFR2. The resulting selective RET inhibitor could maximally block the RET signaling pathway and will increase MTC survival from months to multiple years.

描述（由适用提供）：癌症是美国的第二大死亡原因，迫切需要新的治疗剂来打击该疾病。 1985年，将RET（转染期间重新安排）基因被确定为通过染色体重排激活的新型癌基因。从那时起，RET被确定为几种癌症中的驱动癌基因，尤其是甲状腺癌（MTC）。由于识别选择性RET抑制剂的挑战，MTC的治疗仍然是未满足的医疗需求。为了开发RET激酶抑制剂，已经开发了皮摩尔RET/VEGFR2临床候选者，目前正在临床前研究中。然而，VEGFR2的抑制与促进剂量剂量限制性毒性有关，包括大多数VEGFR2抑制剂药物的患者高血压。我们希望通过消除VEGFR2活性并提高Kinome的整体选择性来进一步开发抑制剂，从而获得最大/或完全抑制患者的RET信号途径。我们将利用经过验证的RET和VEGFR2的计算模型，基于片段的筛选以及潜在的X射线晶体结构信息来开发临床候选者，其临床候选者比VEGFR2进行了30倍RET选择性。由此产生的选择性RET抑制剂可以最大程度地阻断RET信号通路，并将MTC存活率从几个月增加到几年。