Component-based synthesis of Waixenicin A enables TRPM7 inhibitor development

Objective

Waixenicin A (WaixA) is an exceptionally potent, selective inhibitor of TRPM7: the key regulator of cellular Mg(II) homeostasis. As such, it holds promise as a lead compound for treating diseases associated with aberrant TRPM7 activity, such as cancer and neuronal disorders. However, limited access to WaixA has prevented in-depth investigation of its mode of action and pharmacology. This proposal addresses these limitations by providing scalable synthetic access to WaixA (WP1), deciphering its mode of action (WP2), and developing analogs of WaixA with improved efficacy (WP3). WP1 will develop a component-based synthesis of WaixA that constructs the strained (E)-cyclononene via efficient annellation of a linear precursor onto a cyclohexenone fragment using radical or ionic conjugate addition-trapping sequences. WP2 aims to unravel WaixA’s mode of action and binding site through cellular inhibition assays of TRPM7 and cryo-EM structure determination, and proposes an unprecedented, doubly covalent mechanism. WP3 targets second-generation inhibitors of TRPM7 with improved efficacy. These analogs will be synthesised via late-stage diversification in WaixA’s western fragment, or through rigidification of the proposed allylic acetate-pharmacophore or the cyclononene skeleton. Combined, WAIXYN represents the first integrated research effort to study and improve upon the fascinating pharmacophore of WaixA, providing cornerstones for future TRPM7 inhibitor development that can help study and treat diseases associated with aberrant TRPM7 activity in cells and in vivo. A practical synthetic platform to WaixA will enable access to other xenicin natural products and expand the narrow synthetic repertoire for constructing medium-sized carbocycles. WAIXYN will provide extensive training in complex molecule synthesis, foster project leadership, and thus significantly contribute to the researcher's goal of leading a group at the interface of Chemistry and Biology.