Abstract
Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4’ of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC50~1 µM) with moderate selectivity over other kinases.
Highlights
Showed a higher potency as compared to the quinazoline core 5aa. This is in contrast to the nitrogen at the 1-position, which appears to be crucial for the activity since its absence resulted in the inactive analogue 24 while the cinnoline 29 and quinoxaline 34 bearing
The binding between the spautin-1 analogues and Ubiquitin Specific Protease 13 (USP13) was evaluated to confirm that the reduced viability of the epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) cells was caused by inhibition
Since we could not confirm the interaction between Spautin-1 analogues and USP13, a kinase screening was performed using a set of four compounds (Spautin-1 and three analogues) to discover off-targets and identify kinases that are potentially responsible for the reduction in cell viability observed in our screen (Table 2)
Summary
Park activity and co-workers reported, for instance, the NEK4 and moderate selectivity towards expression of NEK4 in lung cancer and suggested that. Cells to TRIAL-induced apoptosis via decreased levels of survivin, an anti-apoptotic proturn results into tumor resistance. Ding and co-workers is a cells to TRIAL-induced apoptosis via decreased levels ofplays survivin, an anti-apoptotic pro regulator epithelial-to-mesenchymal transition (EMT). Reported kinase inhibitors showed positive regulator transition which plays selective described. Some previously reported kinase in- an im good off-target activity for NEK4 but lacked selectivity. There no potent an hibitors showed good off-target activity for NEK4 but lacked selectivity. EGFRlight above, we hypothesize thatactivity the activity our analogues mutant cells is at least in part related to inhibition of NEK4. As far as we EGFR-mutant NSCLC cells is at least in part related to inhibition of NEK4. Show promising single agent anticancer activity towards promising single agent anticancer activity towards EGFR-mutant NSCLC cells
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