Discovery of the next-generation RET-targeted drugs based on nicotinamide scaffold

基于烟酰胺支架的下一代RET靶向药物的发现

• 批准号: 10505815
• 负责人: Herman O Sintim
• 金额: $ 61.21万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505815
• 关键词: Affinity; Benzamides; Biological Markers; Bypass; Cancer Patient; Cancer cell line; Chronic; Clinical; Clinical Research; Collaborations; Data; Dose; Dose-Limiting; Drug Kinetics; Drug Targeting; Drug or chemical Tissue Distribution; Drug resistance; Engineering; Ethers; Evaluation; Excretory function; Exhibits; Gatekeeping; Genes; Goals; Human; Immune checkpoint inhibitor; In Vitro; Intracranial Neoplasms; KDR gene; Laboratory Study; Lead; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thyroid; Metabolism; Metastatic malignant neoplasm to brain; Modeling; Mus; Mutation; Neuraxis; Niacinamide; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Oral; Patients; Pharmaceutical Preparations; Phosphotransferases; Property; Protein Tyrosine Kinase; Regimen; Resistance; Solubility; Solvents; Structure-Activity Relationship; Therapeutic Index; Toxic effect; Transfection; Transgenic Mice; Tumor-Derived; Tyrosine Kinase Inhibitor; United States Food and Drug Administration; absorption; aqueous; base; cancer therapy; clinical candidate; clinical development; design; in vivo; inhibitor; kinase inhibitor; lead optimization; mutant; next generation; novel; novel therapeutics; patient derived xenograft model; pharmacodynamic model; pharmacokinetics and pharmacodynamics; physiologically based pharmacokinetics; pre-clinical; resistance mechanism; response; scaffold; scale up; subcutaneous; targeted treatment; treatment response; tumor; tumor xenograft

Project Summary Human cancers that contain the rearranged-during-transfection (RET) oncogene respond poorly to immune checkpoint inhibitors, but have high response rates to the potent and reasonably selective RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. While selpercatinib and pralsetinib can inhibit RET V804M/L gatekeeper mutants, which are resistant to all other publicly known RET TKIs, the RET G810C/R/S solvent-front mutations have been identified as the major on-target resistant mechanisms to both selpercatinib and pralsetinib. We recently found that TKIs containing alkynyl nicotinamide scaffold were more drug-like than did the corresponding alkynyl benzamides. Through our collaboration, we identified several nicotinamide-based lead compounds that potently inhibit RET, its gatekeeper, solvent front, and roof mutants with selectivity against VEGFR2 and are orally available. These are highly desirable properties for a next-generation RET inhibitor. The long-term goal of this collaborative project is to further characterize the novel nicotinamide-based RET TKIs in order to develop a best-in-class, next-generation potent and selective RET inhibitor that can be used to treat acquired selpercatinib- and pralsetinib-resistant patients in addition to use as the first-line drug for RET-altered cancers. In this project, we will select the best lead compounds through multi-parametric characterization and structure-activity relationship optimization (Specific Aim 1); establish the absorption, distribution, metabolism, excretion, and toxicity (ADMET)-pharmacokinetic (PK) profile and PK/pharmacodynamic (PK/PD) relationship of selected compounds (Specific Aim 2); and evaluate PD biomarkers of kinase inhibition and anti-tumor efficacy of down-selected RET inhibitors in subcutaneous and intracranial tumors derived from engineered and human cancer cell lines, in lung tumors of transgenic mice, and in RET-altered cancer patient-derived xenografts (PDXs) (Specific Aim 3). Through this collaborative, novel multi-parametric selection and optimization effort that incorporates both in vitro and in vivo properties, we expect to obtain one or more potent and selective RET TKIs that are effective on selpercatinib- and pralsetinib-resistant RET mutants and are orally bioavailable with intracranial activity for further clinical development. This will facilitate the effort to increase the duration of tumor response to treatment towards the goal of turning a currently incurable malignancy into a manageable chronic condition, and ultimately a cure.

项目摘要 含有重排干 - 转染（RET）癌基因对免疫反应不佳的人类癌症 检查点抑制剂，但对有效和合理选择性RET蛋白酪氨酸的应答率很高 激酶抑制剂（TKIS）selpercatinib和pralsetinib。而selpercatinib和pralsetinib可以抑制RET V804M/L 守门员突变体，对所有其他公开闻名的RET TKI，RET G810C/r/s溶剂前抗溶剂， 突变已被鉴定为selpercatinib和pralsetinib的主要靶向抗性机制。 我们最近发现，含有烷基烟酰胺的TKI与药物相比，药物比 相应的藻酰胺。通过我们的合作，我们确定了几个基于烟酰胺的铅 有效抑制RET的化合物，其守门人，溶剂前部和屋顶突变体具有选择性 VEGFR2，可以口服。这些是下一代RET抑制剂的高度理想特性。这 这个协作项目的长期目标是进一步描述基于烟酰胺的小说ret tkis 为了开发可用于治疗的一流，下一代有效和选择性的RET抑制剂 除了用作重新替换的一线药物外，还获得了抗甲虫和抗甲替尼的耐药患者 癌症。在这个项目中，我们将通过多参数特征选择最佳的铅化合物和 结构活性关系优化（特定目标1）；建立吸收，分布，代谢， 排泄和毒性（ADMET） - 摄影（PK）概况和PK/Pharmacodynical（PK/PD）的关系 选定的化合物（特定目标2）；并评估激酶抑制和抗肿瘤功效的PD生物标志物 衍生自工程和人类的皮下和颅内肿瘤中的下选择的RET抑制剂 癌细胞系，转基因小鼠的肺部肿瘤，在改变的癌症患者衍生异种移植物（PDXS）中 （特定目标3）。通过这项合作，新颖的多参数选择和优化工作 在体外和体内特性都结合了 对于耐甲虫和抗甲替尼的耐药性RET突变体有效，并且可以口服生物利用 颅内活性，用于进一步的临床发育。这将有助于增加肿瘤持续时间 对治疗的反应，以将当前无法治愈的恶性肿瘤变成可控制的慢性 条件，最终是治愈的。