Small cell lung cancer (SCLC) is a rapidly lethal disease with few therapeutic options. We studied metabolic heterogeneity in SCLC to identify subtype-selective vulnerabilities. Metabolomics in SCLC cell lines identified two groups correlating with high or low expression of the Achaete-scute homolog-1 (ASCL1) transcription factor (ASCL1 and ASCL1), a lineage oncogene. Guanosine nucleotides were elevated in ASCL1 cells and tumors from genetically engineered mice. ASCL1 tumors abundantly express the guanosine biosynthetic enzymes inosine monophosphate dehydrogenase-1 and -2 (IMPDH1 and IMPDH2). These enzymes are transcriptional targets of MYC, which is selectively overexpressed in ASCL1 SCLC. IMPDH inhibition reduced RNA polymerase I-dependent expression of pre-ribosomal RNA and potently suppressed ASCL1 cell growth in culture, selectively reduced growth of ASCL1 xenografts, and combined with chemotherapy to improve survival in genetic mouse models of ASCL1/MYC SCLC. The data define an SCLC subtype-selective vulnerability related to dependence on de novo guanosine nucleotide synthesis.

Neighboring group participation in glycopyranosylation reactions is probed for esters at the 3-Oaxial and equatorial, 4-O-axial and equatorial, and 6-O-sites of a range of donors through the use tert-butoxycarbonyl esters. The anticipated intermediate cyclic dioxanyl cation is interrupted for the axial 3-O-derivative leading to the formation of a 1,3-O-cyclic carbonate ester, with loss of a tertbutyl cation, providing convincing evidence of participation by esters at that position. However, no evidence was found for such a fragmentation of carbonate esters at the 3-O-equatorial, 4-O axial and equatorial and 6-O positions indicating that neighboring group participation from those sites does not occur under typical glycosylation conditions. Further probes employing a 4-O-(2-carboxy) benzoate ester and a 4-O-(4-methoxybenzoate) ester, the latter in conjunction with an 18 O quench designed to detect bridging intermediates, also failed to provide evidence for participation by 4-Oesters in galactopyranosylation.