SignificanceMutants of RAS are major oncogenes and occur in many human cancers, but efforts to develop drugs that directly inhibit the corresponding constitutively active RAS proteins have failed so far. We therefore focused on SOS1, the guanine nucleotide exchange factor (GEF) and activator of RAS. A combination of high-throughput and fragment screening resulted in the identification of nanomolar SOS1 inhibitors, which effectively down-regulate active RAS in tumor cells. In cells with wild-type KRAS, we observed complete inhibition of the RAS-RAF-MEK-ERK pathway. In a mutant KRAS cell line, SOS1 inhibition resulted in a reduction of phospho-ERK activity by 50%. Together, the data indicate that inhibition of GEFs may represent a viable approach for targeting RAS-driven tumors.

Making a mark: Since the 1864 landmark discovery by Adolf von Baeyer, barbituric acids have played a prominent role in organic synthesis. Herein, the first chemoselective monoreduction of barbituric acids to the corresponding hemiaminals is described. The method delivers mono‐ and bicyclic hemiaminal products by a general single‐electron‐transfer polarity reversal mechanism.

The first general reduction of nitriles to primary amines under single electron transfer conditions is demonstrated using SmI2 (Kagan's reagent) activated with Lewis bases. The reaction features excellent functional group tolerance and represents an attractive alternative to the use of pyrophoric alkali metal hydrides. Notably, the electron transfer from Sm(II) to CN functional groups generates imidoyl-type radicals from bench stable nitrile precursors.

Unsaturated, differentially substituted Meldrum's acid derivatives undergo cascade cyclizations upon ester reduction with SmI(2)-H(2)O. The cascade cyclizations proceed in good yield and with high diastereocontrol and convert simple, achiral starting materials to complex molecular architectures, bearing up to four stereocenters, in a single operation. The cascades are triggered by the generation and trapping of unusual radical-anions formed by electron transfer to the ester carbonyl.