The enzyme phosphoinositide 3-kinase (PI3K) plays a central role in the cellular response to growth factors and receptor activation through activation of downstream effectors such as Akt and mTOR . PI3K is involved in protein synthesis, cell proliferation, survival and multiple drug
resistance mechanisms in cancer cells [2,3]. Several signalling molecules in the PI3K/Akt pathways are frequently mutated, deleted or amplified in human cancer including PI3K, PTEN, and Akt . Treatment with PI3K inhibitors as single agents can inhibit cancer cell proliferation and induce
apoptosis and cell death. The combination of PI3K inhibitors with other therapeutic agents has often synergistic effects on tumor growth inhibition in experimental models and in some clinical trials . The inhibition of PI3K signalling therefore provides a strong lead to improve cancer treatment.
Currently, there are promising PI3K inhibitors in clinical trials to treat human cancer . The immediate future challenge is to determine whether or how these PI3K inhibitors can be applied in a highly tumour-specific way with little adverse effects and how to select the most sensitive patients
among different genetic backgrounds. The increasing importance of PI3K-dependent signalling as a cancer target has generated a large number of therapeutics targeting the PI3K/Akt pathways. Despite the surge of expectations elicited by their promising preclinical data, preliminary clinical
results obtained so far with PI3K pathway inhibitors have not fulfilled their promises especially if considered as single-agent. Among the different explanations it is possible that this is due to insufficient inhibition of the target or to the fact that PI3K inhibition is simply not
sufficient to stop tumor growth. Nevertheless, the clinical testing of PI3K pathway inhibitors is still in its infancy and requires a concerted tuning of strategies and approaches. On this basis, novel aspects of pharmacology and drug development of PI3K pathway inhibitors are the
focus of this Hot Topic issue of Current Medicinal Chemistry. This is a timely topic, as there is tremendous interest in the therapeutic development of PI3K inhibitors. As a consequence of the increasing interest around PI3K pathways, during the last few years, there have been several
reviews on PI3K signaling and on PI3K pathway inhibitors. Therefore, to avoid inevitable overlapping and repetitions I decided to concentrate the attention of this Hot Topic on the ultimate challenges that lay ahead in this scientific field. In order to distinguish themselves, Ciraolo et al.,
have focused on describing the pharmacology of the developmental compounds, preliminary clinical findings and potential side effects based on research mainly from genetic studies . Shuttleworth et al. provide a comprehensive review of the recent development of compounds targeting the
class I PI3Ks and also compounds that target both the class I PI3-Ks and mTOR . Much of the data that the authors summarize is from patents and meeting abstracts and therefore absent from the general scientific literature. The cancer stem cell hypothesis is generating a great deal of interest
because of its potential clinical implications, as it indicates that the route for cancer eradication will require the use of strategies which expunge the root cause of the tumour . The findings reviewed in one article of this Hot Topic, strongly suggest that increased PI3K/Akt/mTOR signalling
activity is important to regulate some of the cancer stem cells properties, including resistance to chemotherapy and radiotherapy . Finally, three articles focused their attention on key downstream targets of PI3K, namely Akt, mTOR and PDK1, discussing strategies used to develop novel
kinase inhibitors [10-12]. Overall, I hope the articles of this Hot Topic can represent a useful instrument for the broad readership of Current Medicinal Chemistry to become acquainted with signal transduction pathways that have emerged as important therapeutic targets in the context
of cancer and the exciting and promising small molecule discovery research in the PI3K field.
Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.