Molecular Glues to Target RAS-MAPK Driven Cancers

分子胶靶向 RAS-MAPK 驱动的癌症

基本信息

批准号：
10880005
负责人：
Arvin Dar
金额：
$ 35.63万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10880005
关键词：
Active Sites Aging BRAF gene Benchmarking Binding Binding Sites Biological Assay Biology Cancer Model Cell Line Cells Chemicals Clinical Colorectal Cancer Complex Data Development Diagnosis Drug Kinetics Drug Receptors Drug Targeting Drug resistance Excretory function Extracellular Signal Regulated Kinases Feedback Genetic study Glues Homologous Gene Human Immunotherapy In Vitro Individual KRAS2 gene KSR gene Laboratories Ligands MAP Kinase Gene MEKKs Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolism Microsomes Mitogen-Activated Protein Kinase Inhibitor Modality Molecular Mus Mutate Nature Oncogenes Oncogenic Oncology Organoids Parents Pathway interactions Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Phenotype Phosphotransferases Physiological Predisposition Property Protein Family Protein Kinase Proteins Publishing Ras/Raf Rationalization Resistance Roentgen Rays Role Safety Series Signal Transduction Structure Testing Therapeutic Therapeutic Index Time Toxic effect Work X-Ray Crystallography Xenograft procedure absorption analog antagonist combinatorial design effective therapy efficacy evaluation improved in silico in vivo inhibitor insight interfacial next generation novel novel drug class novel therapeutics paralogous gene pharmacologic pharmacophore pre-clinical receptor binding residence resistance mechanism response scaffold small molecule targeted treatment therapeutic development tool treatment duration triple-negative invasive breast carcinoma tumor

项目摘要

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.

概括我们寻求通过靶向界面结合来开发一类针对 RAS-MAPK 驱动的癌症的新型药物级联内关键调控复合物的位点通过摆脱传统的基于活性位点的方式。药物，我们有潜力开发一类独特的化合物，在选择性、靶点方面具有优势参与、治疗指数和组合活动，以减轻耐药性的出现。 MAPK/ERK 激酶 (MEK) MEK 是 KRAS 和 BRAF 的共享效应器，它们是最重要的效应器之一。所有人类癌症中致癌基因和蛋白激酶都经常发生突变，因此，MEK 长期以来一直是人们关注的焦点。作为肿瘤学的药物靶标，最近也被用于免疫治疗和衰老。由于与目标相关的毒性和耐药性，目标 MEK 受到限制。对生理复合物中 MEK 结构和功能的分子理解可以提供我的实验室已在这方面迈出了初步的步伐。通过确定与 RAF 旁系同源激酶结合的 MEK 的 X 射线晶体结构来确定方向 Ras 抑制剂 (KSR)，并与各种 MEKi 复合，包括第一个共晶结构与临床药物曲美替尼（Trametinib）结合（Khan 等人，Nature，2020）与大多数靶向疗法不同，曲美替尼（Trametinib）是通过表型筛选偶然发现的，但我们的小说缺乏 X 射线晶体结构。结构和功能的见解揭示了一种意想不到的结合模式，其中抑制剂口袋 Trametinib 是通过 MEK 和 KSR 之间的界面形成的，表明 KSR 是 MEK 的直接共受体。此外，我们的研究表明，药物和曲美替尼作为“界面粘合剂”具有独特的治疗作用。曲美替尼的特性源自药物在复合物界面上的结合能力。根据这些见解，我们开发了一种工具化合物曲美胶，具有增强的界面结合特性以及一些新颖的药理学特征，包括前所未有的效力和克服困难的能力 Trametinib 和其他临床 MEKi 的常见耐药机制该提案重点开发一种药物。通过基于结构的设计和合成获得先进的类似物集，我们的目标包括先进的。曲美胶类似物，包括针对单个 MAPK 信号传导的旁系同源选择性分子胶与 RAS-MAPK 驱动的癌症有关的复合物以及对现有药物的敏感性（目标 1）。通过这组扩展的类似物进行体内靶标接合和类药物特性的优化。（目标 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 KRAS-G12C 和 BRAF-V600E 抑制剂等治疗取得了突破，但 90% 的 RAS-MAPK 肿瘤是无法实施的，该提案的进展将导致下一代药物和药物的研发。一种选择性拮抗患者 RAS-MAPK 驱动的恶性肿瘤的新治疗方式。