Abstract
GTPases and kinases are two predominant signaling modules that regulate cell fate. Dysregulation of Ras, a GTPase, and the three eponymous kinases that form key nodes of the associated phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K)/AKT/mTOR pathway have been implicated in many cancers, including pancreatic cancer, a disease noted for its current lack of effective therapeutics. The K-Ras isoform of Ras is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC) and there is growing evidence linking aberrant PI3K/AKT/mTOR pathway activity to PDAC. Although these observations suggest that targeting one of these nodes might lead to more effective treatment options for patients with pancreatic and other cancers, the complex regulatory mechanisms and the number of sequence-conserved isoforms of these proteins have been viewed as significant barriers in drug development. Emerging insights into the allosteric regulatory mechanisms of these proteins suggest novel opportunities for development of selective allosteric inhibitors with fragment-based drug discovery (FBDD) helping make significant inroads. The fact that allosteric inhibitors of Ras and AKT are currently in pre-clinical development lends support to this approach. In this article, we will focus on the recent advances and merits of developing allosteric drugs targeting these two inter-related signaling pathways.
Highlights
Dysregulation of cellular signaling pathways that involve phosphoryl transfer through GTPase and kinase activities is a key step in the initiation and development of neoplasms (Hanahan and Weinberg, 2011)
Among the GTPases, constitutive Ras activation plays a critical role in the development of pancreatic, colon, and lung cancers, and is an indicator of poor prognosis (Kim et al, 2006; Califano et al, 2012; Pérez-Ruiz et al, 2012), with the Kristin isoform of Ras (K-Ras) being mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC) (Morris et al, 2010)
Selective PI3K inhibition by allosteric means may soon emerge from recent reports that have begun to decipher the activation mechanism of these enzymes (Burke et al, 2012; Hon et al, 2012)
Summary
Dysregulation of cellular signaling pathways that involve phosphoryl transfer through GTPase and kinase activities is a key step in the initiation and development of neoplasms (Hanahan and Weinberg, 2011). As with Ras, computational chemistry techniques and FBDD have helped develop some promising new avenues in selectively targeting various isoforms (Giordanetto et al, 2011, 2012; Hughes et al, 2011), albeit through competitive inhibitors that bind the active site.
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