Molecular Glues to Target RAS-MAPK Driven Cancers

总结 我们寻求通过靶向RAS-MAPK的界面结合来开发一类新的药物用于RAS-MAPK驱动的癌症。 级联中关键调控复合物的位点。通过摆脱传统的基于活性位点的 药物，我们有潜力的一个独特的一类化合物的优势，在选择性，目标 结合、治疗指数和组合活性以减轻耐药性的出现。 MAPK/ERK激酶（MEK）MEK是KRAS和BRAF的共有效应子，它们是最常见的细胞因子之一。 在所有人类癌症中频繁突变的癌基因和蛋白激酶。因此，长期以来， 作为肿瘤学中的药物靶点，最近在免疫治疗和衰老中也是如此。然而，许多药物 靶向MEK由于靶向相关毒性和耐药性而受到限制。因此 对MEK在生理复合物中的结构和功能的分子理解可以提供 设计更安全、更有效疗法的模板。我的实验室已经在这方面迈出了初步的步伐 通过测定结合至RAF Parkinase激酶的MEK的X射线晶体结构， Ras抑制剂（KSR），并与各种MEKi复合，包括第一次共晶结构 与临床药物曲美替尼结合（Khan等人，Nature，2020）。与大多数靶向治疗不同，曲美替尼 通过表型筛选偶然发现，缺乏X射线晶体结构。我们的新型 结构和功能的见解已经揭示了一种意想不到的结合模式，其中抑制剂口袋， 曲美替尼是通过MEK和KSR之间的界面形成的，揭示了KSR作为药物的直接共受体。 药物和曲美替尼作为“界面粘合剂”。此外，我们的研究表明， 曲美替尼的性质来源于药物在复合物界面结合的能力。建筑从 基于这些见解，我们开发了一种工具化合物，曲美替胶，具有增强的界面结合性能 和几个新的药理学特征，包括前所未有的效力和克服 对曲美替尼和其他临床MEKi的常见耐药机制。该提案的重点是制定一项 通过基于结构的设计和合成的先进的类似物。我们的目标包括先进的 曲美替格类似物，包括靶向单个MAPK信号传导的旁系同源选择性分子胶 与RAS-MAPK驱动的癌症和对目前可用药物的敏感性有关的复合物 (Aim 1）。用这种扩展的类似物组进行体内靶向接合和药物样性质的优化 (Aim 2）。在临床前癌症模型中进行测试，包括患者来源的类器官和异种移植物（目标3）。 全球每年有超过500万人被诊断患有RAS-MAPK驱动的癌症。 尽管最近的治疗突破，例如KRAS-G12 C和BRAF-V600 E抑制剂， 90%的RAS-MAPK肿瘤是不可手术的。这一提议的进展将导致下一代药物的产生， 选择性拮抗RAS-MAPK驱动的恶性肿瘤患者的新的治疗模式。

SUMMARY We seek to develop a new class of drugs for RAS-MAPK driven cancers by targeting the interfacial binding sites of key regulatory complexes within the cascade. By moving away from conventional active site-based drugs, we have the potential for a unique class of compounds with advantages in terms of selectivity, target engagement, therapeutic index, and combinatorial activity to mitigate the emergence of drug resistance. The MAPK/ERK Kinase (MEK) MEK is a shared effector of KRAS and BRAF, which are among the most frequently mutated oncogenes and protein kinases across all human cancers. As such, MEK has long been pursued as a drug target in oncology, and more recently in immunotherapy and aging. However, many drugs that target MEK are limited due to on-target associated toxicities and drug resistance. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. My laboratory has made initial steps in this direction through the determination of X-ray crystal structures of MEK bound to the RAF paralog Kinase Suppressor of Ras (KSR), and in complex with various MEKi, including the first ever co-crystal structures bound to the clinical drug trametinib (Khan et al., Nature, 2020). Unlike most targeted therapies, trametinib was serendipitously identified through phenotypic screens, and X-ray crystal structures had been lacking. Our novel structural and functional insights have revealed an unexpected mode of binding in which the inhibitor pocket for trametinib is formed through the interface between MEK and KSR, revealing KSR as a direct co-receptor of the drug and trametinib as an ‘interfacial binder’. Moreover, our studies suggest that the unique therapeutic properties of trametinib derive from the ability of the drug to bind at the interface of the complex. Building from these insights, we have developed a tool compound, trametiglue, with enhanced interfacial binding properties and several novel pharmacological features, including unprecedented potency and an ability to overcome a common resistance mechanism to trametinib and other clinical MEKi. This proposal focuses on developing an advanced set of analogs through structure-based design and synthesis. Our targets include advanced trametiglue analogs, including paralog-selective molecular glues to target individual MAPK signaling complexes that have been implicated in RAS-MAPK driven cancers and sensitivity to currently available drugs (Aim 1). In vivo target engagement and optimization of drug-like properties with this expanded set of analogs (Aim 2). Testing in preclinical cancer models, including patient derived organoids and xenografts (Aim 3). There are over 5 million individuals diagnosed globally with RAS-MAPK driven cancers on a yearly basis. Despite recent therapeutic breakthroughs with, for example KRAS-G12C and BRAF-V600E inhibitors, over 90% of RAS-MAPK tumors are unactionable. Advances in this proposal will lead to next generation drugs and a new therapeutic modality for selectively antagonizing RAS-MAPK driven malignancies in patients.