Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits.

Highlights d Clustering of kinome by inhibition phenotype identifies promiscuous kinases d Promiscuous tyrosine kinases are stable in the DFG-Asp-out inactive conformation d Residues define promiscuous kinases and stabilize inactive conformation

Introduction: The risk for development of a second primary lung cancer (SPLC) after treatment of an initial primary lung cancer (IPLC) is around 1% to 2% per patient per year. The present screening and surveillance guidelines do not adequately address this particular patient population. Methods: We retrospectively reviewed patients in the Surveillance, Epidemiology, and End Results database from 1992 to 2007 to assess the frequency of occurrence of SPLC with regard to multiple patient demographics and calculated standardized incidence ratios (SIRs). Results: The SIRs for SPLCs were high for both men and women at any age but highest if the IPLC occurred at a younger age. Women had the highest SIR values irrespective of age and race, with the highest SIR reported for the youngest age group (20–49 years) (SIR = 15.26, 95% confidence interval: 12.81–18.04). The rate of SPLC development was 1.10% per patient per year, with median time intervals between the IPLC and SPLC diagnoses of 59 and 62 months, respectively, for men and women. The cumulative risk for development of SPLC increased over time and did not plateau. Conclusions: These findings suggest that there is a continued risk for development of SPLC. Surveillance strategies for this population must be addressed.

XIAP, a member of the inhibitor of apoptosis family of proteins, is a critical regulator of apoptosis. Inhibition of the BIR domain-caspase interaction is a promising approach towards treating cancer. Previous work has been directed towards inhibiting the BIR3-caspase-9 interaction, which blocks the intrinsic apoptotic pathway; selectively inhibiting the BIR2-caspase-3 interaction would also block the extrinsic pathway. The BIR2 domain of XIAP has successfully been crystallized; peptides and small-molecule inhibitors can be soaked into these crystals, which diffract to high resolution. Here, the BIR2 apo crystal structure and the structures of five BIR2-tetrapeptide complexes are described. The structural flexibility observed on comparing these structures, along with a comparison with XIAP BIR3, affords an understanding of the structural elements that drive selectivity between BIR2 and BIR3 and which can be used to design BIR2-selective inhibitors.