Background:The PAKs are effectors of Rac/cdc42. Results: Identification of a pyridopyrimidinone, as a potent inhibitor of the group I PAKs that shows anti-tumor activity in vivo. Conclusion: A pyridopyrimidinone provides a scaffold for development of high specificity group I PAK inhibitors. Significance: Identification class of orally available ATP-competitive Group I PAK inhibitors with significant potential for the treatment of NF2.

The Notch pathway has been implicated in a number of malignancies with different roles that are cell and tissue-type dependent. Notch1 is a putative oncogene in NSCLC and activation of the pathway represents a negative prognostic factor. To establish the role of Notch1 in lung adenocarcinoma we directly assessed its requirement in K-ras-induced tumorigenesis in vivo, employing an autochthonous model of lung adenocarcinoma with concomitant expression of oncogenic K-ras and deletion of Notch1. We find that Notch1 function is required for tumor initiation via suppression of p53-mediated apoptosis, through the regulation of p53 stability. These findings implicate Notch1 as a critical effector in K-ras-driven lung adenocarcinoma and as a regulator of p53 at a post-translational level. Moreover, our study provides new insights to explain, at a molecular level, the correlation between Notch1 activity and poor prognosis in NSCLC patients carrying wild type p53. This information is critical for design and implementation of new therapeutic strategies in this cohort of patients representing 50% of NSCLC cases.