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: 10652630
• 负责人: FUNDA MERIC-BERNSTAM
• 金额: $ 56.79万
• 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/10652630
• 关键词: Affinity; Benzamides; Biological Availability; Biological Markers; Bypass; Cancer Patient; Cancer cell line; Central Nervous System; Central Nervous System Neoplasms; 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; 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; cancer therapy; 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.

项目概要 含有转染期间重排 (RET) 癌基因的人类癌症对免疫反应较差 检查点抑制剂，但对有效且合理选择性的 RET 蛋白酪氨酸有很高的反应率 激酶抑制剂 (TKI) selpercatinib 和 pralsetinib。而selpercatinib和pralsetinib可以抑制RET V804M/L 看门人突变体，对所有其他众所周知的 RET TKI、RET G810C/R/S 溶剂前沿具有抗性 突变已被确定为 selpercatinib 和 pralsetinib 的主要靶向耐药机制。 我们最近发现含有炔基烟酰胺支架的 TKI 比含炔基烟酰胺支架的 TKI 更像药物。 相应的炔基苯甲酰胺。通过我们的合作，我们确定了几种基于烟酰胺的先导化合物 有效抑制 RET、其看门人、溶剂前沿和屋顶突变体的化合物，并具有选择性 VEGFR2 和 可以口服。这些是下一代 RET 抑制剂非常理想的特性。这 该合作项目的长期目标是进一步表征基于烟酰胺的新型 RET TKI 为了开发一种一流的、下一代有效的、选择性的 RET 抑制剂，可用于治疗 除了用作 RET 改变的一线药物外，还获得了对 selpercatinib 和 pralsetinib 耐药的患者 癌症。在这个项目中，我们将通过多参数表征和分析来选择最好的先导化合物 构效关系优化（具体目标1）；建立吸收、分布、代谢、 排泄和毒性 (ADMET)-药代动力学 (PK) 概况以及 PK/药效 (PK/PD) 关系 选定的化合物（具体目标 2）；并评估PD激酶抑制和抗肿瘤功效的生物标志物 皮下和颅内肿瘤中下调选择的 RET 抑制剂的研究 癌细胞系、转基因小鼠的肺肿瘤以及 RET 改变的癌症患者来源的异种移植物 (PDX) （具体目标 3）。通过这种协作、新颖的多参数选择和优化工作， 结合了体外和体内特性，我们期望获得一种或多种有效且选择性的 RET TKI 对 selpercatinib 和 pralsetinib 耐药的 RET 突变体有效，并且口服生物可利用 颅内活动用于进一步的临床开发。这将有利于延长肿瘤持续时间 对治疗的反应，以期将目前无法治愈的恶性肿瘤转变为可控制的慢性病 病情，最终治愈。