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PDF file - 232K, Immunohistochemical analysis of P-Erk, P-Akt, P-S6, and beta-catenin in tumors arising in K5-tTR::tet-Kras mice

The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream of Ras, in particular Raf/Mek/Erk and PI3K/Akt/mTOR, are dominated by lipid and protein kinases that provide attractive alternate targets in Ras-driven tumors. As p21-activated kinase 1 (Pak1) has been shown to regulate both these signaling pathways and is itself upregulated in many human cancers, we assessed the role of Pak1 in Ras-driven skin cancer. In human squamous cell carcinoma (SCC), we found a strong positive correlation between advanced stage and grade and PAK1 expression. Using a mouse model of Kras-driven SCC, we showed that deletion of the mouse Pak1 gene led to markedly decreased tumorigenesis and progression, accompanied by near total loss of Erk and Akt activity. Treatment of KrasG12D mice with either of two distinct small molecule Pak inhibitors (PF3758309 and FRAX597) caused tumor regression and loss of Erk and Akt activity. Tumor regression was also seen in mice treated with a specific Mek inhibitor, but not with an Akt inhibitor. These findings establish Pak1 as a new target in KRAS-driven tumors and suggest a mechanism of action through the Erk, but not the Akt, signaling pathway. Cancer Res; 72(22); 5966–75. ©2012 AACR.

PDF file - 99K, Immunostaining for Pak1 and Pak2 in mouse skin

PDF file - 60K, Schematic presentation of Ras-mediated Pak1 signaling

PDF file - 162K, Proliferation and apoptosis in drug-treated animals

PDF file - 153K

PDF file - 289K, Immunostaining of Pak1 and proliferative signaling markers in SCC

PDF file - 126K, Activity of FRAX-597 against group A and group B Paks

PDF file - 58K, Specificity of Pak inhibitors

PDF file - 219K, Immunostaining for Pak1 and Pak2 in mouse skin

PDF file - 131K

A convergent synthesis of (−)-crambidine is reported. The sequence capitalizes on two novel key transformations, including a [4+2] annulation of thioimidates with vinyl carbodiimides and an alkyne hydroamination employing 2-aminopyrimidine nucleophiles.

A diastereoselective [4 + 2]-annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich polycyclic guanidine cores of the batzelladine alkaloids. Application of this strategy, together with additional key steps such as long-range directed hydrogenation and diastereoselective intramolecular iodo-amination, led to highly convergent total syntheses of (-)-batzelladine D and (+)-batzelladine A with excellent stereocontrol.

A diastereoselective [4+2] annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich tricyclic core of the batzelladine alkaloids. Its application to the asymmetric synthesis of batzelladine D permitted the use of long-range, directed hydrogenation and stereoselective intramolecular iodoamination as additional key steps to establish the remaining stereocenters within the natural product with excellent stereocontrol.