Molecular Glues to Target RAS-MAPK Driven Cancers

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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.