The paralytic agent (+)-saxitoxin (STX), most commonly associated with oceanic red tides and shellfish poisoning, is a potent inhibitor of electrical conduction in cells. Its nefarious effects result from inhibition of voltage-gated sodium channels (Na(V)s), the obligatory proteins responsible for the initiation and propagation of action potentials. In the annals of ion channel research, the identification and characterization of Na(V)s trace to the availability of STX and an allied guanidinium derivative, tetrodotoxin. The mystique of STX is expressed in both its function and form, as this uniquely compact dication boasts more heteroatoms than carbon centers. This Review highlights both the chemistry and chemical biology of this fascinating natural product, and offers a perspective as to how molecular design and synthesis may be used to explore Na(V) structure and function.

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Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of “bi-steric inhibitors” that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRASG12C shows increased antitumor activity in a preclinical model of KRAS G12C mutant NSCLC that exhibits resistance to KRASG12C inhibitor monotherapy.

An intramolecular thioester-olefin cross-coupling reaction for the preparation of cyclic ketone structures from unsaturated thioesters is described. This method capitalizes on the unique reactivity of thioesters with low-valent palladium catalysts and copper(I) salts to form acyl-metal species. Trapping of such intermediates with alkene functional groups generates the corresponding exo-methylene cycloalkanone products. Unsaturated thioester substrates, which can be accessed using a suite of modern synthetic methods, can now be regarded as precursors to complex carbocyclic derivatives. Fig. 1 A palladium-catalyzed thioester carbocylization reaction.