The phosphoinositide 3-kinase (PI3K)/AKT1 pathway is acknowledged as a key component of cell survival. Activated by receptors or the small GTPase Ras, the various PI3K isoforms phosphorylate inositol lipids to form second messenger phosphoinositides. PI3K family members have long been accepted as oncogenes. An increase in copy number of specific PI3K genes or molecular mutation of these genes, leads to a ‘gain of function’ reflected by a higher or a constitutive activation of PI3K activity and to the oncogenic transformation of many cell types.

PI3K is now viewed as a key player in many aspects of cell motility and adhesion and hence it is able to contribute to metastatic/invasive phenotypes of various cancer cells. Initial work on PI3K was however more focused on its function in cell growth and transformation and it is now clear that indirect or direct deregulation of PI3K causes aberrant cell-cycle progression and transformation of normal cells into tumor cells.

As well as playing a role in abnormal proliferation, PI3K is central to cell survival. Initial evidence was based on the ability of wortmannin to cause apoptosis in PC12 cells. The mechanism by which PI3K protects cells from programmed cell death has been the subject of intensive research and involves the downstream activation of the protein kinase Akt. PtdIns(3,4)P2 and PtdIns(3,4,5)P3 lipids produced by PI3K are able to bind Akt recruiting it to the plasma membrane where PDK1 and PDK2 phosphorylate it to its active form. This allows Akt to target proteins involved in cell death including members of the Bcl-2 family and caspase-9, protecting cells from apoptosis. In addition PI3K activation is able to increase the expression of members of the "Inhibitors of Apoptosis" family such as the c-IAPs (for a full analysis of this family Click here).

Disruption of the apoptotic pathways may account for resistance to chemotherapy and treatment failures in human neoplastic disease. Such treatment failure is well exemplified by acute promyelocytic leukemia. This cancer is responsive to both cytotoxic drugs that act through the stimulation of apoptosis as well as differentiating therapies, primarily retinoic acid (Click here to access our recent overview of retinoid therapeutics). Unfortunately however, remission is frequently only transient. The development of therapeutic approaches that overcome drug resistance is therefore of primary importance and in this respect considerable attention is being paid to the identification of p-glycoprotein inhibitors.

Due to the constitutive activation of PI3K in many cancers and the role of this enzyme in multiple aspects of cancer progression, inhibition of this enzyme has been investigated as a treatment for cancer. Moreover it is possible that PI3K inhibitors could serve to overcome drug resistance. To investigate this concept Italian researchers have recently investigated the effects of two inhibitors of PI3K, wortmannin and Ly294002, on the sensitivity of a drug resistant HL-60 clone to retinoic acid and pro-apoptotic molecules.

This clone was characterized by an increase in PI3K activity. Both wortmannin and Ly294002 were found to reduce phosphatidylinositol (3,4,5) trisphosphate levels and AKT1 activity and also to reverse resistance to several pro-apoptotic drugs (Camptothecin, Etoposide, Doxorubicin, Cytarabine, Mitoxantrone and Vincristine). Similarly, resistant cells overexpressing either dominant negative PI3K or dominant negative AKT1 became sensitive to these drugs. Conversely, if parental HL-60 cells were forced to over-express an activated AKT1, they became resistant to apoptotic drugs. This suggests that PI3K inhibitors can reintroduce sensitivity to apoptotic molecules.

Likewise, the inhibition of PI3K dramatically reintroduced sensitivity of the HL-60 cells to retinoic acid. Together therefore, these data strongly implicate PI3K and its down-stream signaling pathway in drug resistance in myeloid leukemia and suggests that PI3K inhibitors may be of particular therapeutic benefit. Due to the wide-ranging involvement of PI3K in many different aspects of tumor progression, the therapeutic benefit of such molecules is expected to extend to multiple types of cancer. Despite this potential however, little activity has been reported regarding the development of candidate PI3K inhibitors.

In order to help speed the development of kinase inhibitors, ChemOvation, a leading provider of medicinal chemistry services to both pharmaceuticals and biotechnology sectors has designed a “Kinase Enterprise Library”. This library was designed using proprietary informatics tools, and represents a diverse collection of compounds based on 15 different templates. The potential importance of this library is increased by also including modelling filters such as AMDE and physio-chemical parameters. The templates are unique to ChemOvation and are available on a non-exclusive basis through LeadDiscovery's PharmaceuticalSolutions service. This library can be supplied for in house screening for PKI3 inhibitors or alternatively screening can be performed by Chemovation. In either case follow of services are offered to optimize hits.

Entry date March, 2003

Adapted from Neri et al, Mol Cancer Res 2003 Jan;1(3):234-46 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk