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

项目摘要 含有RET癌基因的人类癌症对免疫反应较差 检查点抑制剂，但对有效和合理选择的RET蛋白酪氨酸有很高的应答率 激酶抑制剂(TKI)赛培卡替尼和普罗塞替尼。塞培卡替尼和普拉塞替尼对RET V804M/L的抑制作用 看门人突变体，对所有其他公知的RET TKI具有抵抗力，RET G810C/R/S溶剂前沿 突变已被确定为赛培卡替尼和普拉塞替尼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 相应的炔基苯甲酰胺。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、其看门人、溶剂前沿和屋顶突变体的化合物，对 VEGFR2和口服给药。这些都是下一代RET抑制剂非常理想的特性。这个 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 TKIs在 为了开发一种同类最好的，下一代有效的和选择性的RET抑制剂，可以用于治疗 获得性赛培卡替尼和普拉塞替尼耐药患者除用作RET改变的一线药物外 癌症。在这个项目中，我们将通过多参数表征和 构效关系优化(特定目标1)；建立吸收、分布、代谢、 排泄和毒性(ADMET)-药代动力学(PK)谱和PK/药效学(PK/PD)关系 精选化合物(特定目标2)；并评价抑制激酶活性和抗肿瘤疗效的PD生物标志物 下选择的RET抑制剂在工程和人类来源的皮下和颅内肿瘤中的作用 肿瘤细胞系，在转基因小鼠的肺癌中，在RET改变的癌症患者来源的异种移植(PDX)中 (具体目标3)。通过这种协作、新颖的多参数选择和优化工作， 结合了体外和体内的特性，我们希望获得一种或多种有效的和选择性的RET TKI 对赛培卡替尼和普拉塞替尼耐药的RET突变体有效，口服生物利用度 为进一步的临床发展提供更多的颅内活动。这将有助于努力延长肿瘤的持续时间。 对治疗的反应，以实现将目前无法治愈的恶性肿瘤转变为可控慢性疾病的目标 病情，并最终治愈。

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.