Dual-Mechanism Allosteric Inhibitors of ERK Signaling

总结 目前没有FDA批准的靶向ERK通路的药物，其中RAS 突变驱动ERK活性。长期目标是帮助开发治疗上有用的ERK 用于恶性肿瘤临床治疗的抑制剂。本申请的总体目标是 （i）表征化学和变构机制，并开发一类新的共价键， ERK抑制剂，（ii）阐明它们诱导抗增殖性细胞因子的分子机制。 与FDA批准的垂直靶向ERK途径的药物组合的活性，和（iii） 测定使用患者来源的类器官的组合治疗的体内抗肿瘤功效 和肿瘤模型。中心假设是，使用共价、变构 ERK的抑制剂可以被开发为具有诱导凋亡性细胞死亡的合适效力 并在预测临床疗效的患者来源的肿瘤模型中促进肿瘤消退。的 该项目的基本原理是，开发一种新的化学策略来抑制ERK和确定 它的临床前治疗效果和相关机制可能会提供一个强大的科学 开发新的癌症治疗方法的框架。检验中心假设 通过追求两个具体目标发生：1）ERK机制的设计和阐明 募集位点抑制剂和2）研究患者源性CRC中的共价ERK抑制剂 肿瘤模型。第一个目标是优化一类新的共价变构ERK抑制剂， 描绘变构结合和抑制机制，以确定高度特异性的线索。第二 目的通过RAS-和RAF-的诱导，阐明ERK抑制的机制和后果。 转换患者衍生模型，并确定与FDA批准的 靶向ERK通路的药物诱导肿瘤消退。申请人认为， 本申请中提出的研究是创新的，因为它侧重于从 一类新的ERK抑制剂化合物，其共价靶向ERK上的蛋白质结合位点。 这些化合物将表现出改善的药效学和阻断代偿性反馈 并诱导持久的ERK抑制，以促进强大的细胞毒性抗- 癌症影响。这项研究意义重大，因为它有望提供大量的 新型ERK抑制剂的持续开发和未来临床试验的科学依据 治疗最终，这些知识可以为发展 治疗癌症的创新疗法。

SUMMARY There are currently no FDA-approved drugs available targeting the ERK pathway in which RAS mutations drive ERK activity. The long-term goal is to help develop therapeutically useful ERK inhibitors for the clinical treatment of malignancies. The overall objectives in this application are to (i) characterize the chemical and allosteric mechanism and develop a novel class of covalent ERK inhibitors, (ii) elucidate the molecular mechanism(s) by which they induce anti-proliferative activity in combination with FDA-approved drugs vertically targeting the ERK pathway and (iii) determine the in vivo anti-tumor efficacy of combination treatments using patient-derived organoid and tumor models. The central hypothesis is that combination therapy using covalent, allosteric inhibitors of ERK can be developed to possess suitable potency to induce apoptotic cell death and promote tumor regression in patient-derived tumor models predictive of clinical efficacy. The project's rationale is that developing a new chemical strategy to inhibit ERK and determination of its preclinical therapeutic efficacy and associated mechanisms is likely to offer a robust scientific framework for developing new cancer therapeutic approaches. Testing the central hypothesis occurs by pursuing two specific aims: 1) The design and elucidation of the mechanism of ERK recruitment site inhibitors and 2) investigating covalent ERK inhibitors in patient-derived CRC Tumor Models. The first aim is to optimize a new class of covalent allosteric ERK inhibitors and delineate allosteric binding and inhibition mechanisms to identify highly specific leads. The second aim delineates ERK inhibition's mechanisms and consequences by leads in RAS- and RAF- transformed patient-derived models and identifies agents that, combined with FDA-approved drugs targeting the ERK pathway, induce tumor regression. In the applicant's opinion, the research proposed in this application is innovative because it focuses on developing leads from a new class of ERK inhibitor compounds that covalently target a site of protein binding on ERK. These compounds will exhibit improved pharmacodynamics and block compensatory feedback signals from ERK signaling and induce durable ERK inhibition to promote robust cytotoxic anti- cancer effects. The proposed research is significant because it is expected to provide substantial scientific justification for the continued development and future clinical trials of novel ERK inhibitor therapies. Ultimately, such knowledge can offer new opportunities for the development of innovative therapies to treat cancer.