In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8) and amber score (−51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development.     

Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.