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BEZ235: THE FIRST PI3K INHIBITOR INTO CLINICAL TRIALS

by Selleckchem | Mar 19 2012

Introduction: PI3K inhibition

Currently in clinical testing are inhibitors of both Akt and mTOR which have shown significant promise for certain patient sub-populations. However, resistance and toxicity to these molecules is common, hence new targets are continuously being investigated. Upstream of Akt and mTOR is the membrane bound protein PI3K which intercepts signals from extracellular growth factor from transmission into the cytosole and eventually the nucleus. While being an upstream target PI3K is still being investigated for anti-tumor effects (1, 2). PI3K is classified into several classes with class 1 being the focus of the small molecule inhibitors currently in preclinical and clinical testing (3). Class 1 kinases are subdivided into four different proteins containing a common catalytic domain, they are identified as Alpha, Beta, Gamma and Delta (4). BEZ235 PI3K inhibitor is a pan- inhibitor of all the isoforms of PI3K as well as targeting mTOR directly as well. BEZ235 is known as an effective dual inhibitor of many tumor types (5-11).

BEZ235: Properties and Availability

Developed by Novartis the dual inhibitor BEZ235 can be found in the catalogues of several BEZ235 suppliers with BEZ235 prices ranging from $35 up to $475 for a 50 mg vial. BEZ235 solubility in water is typical for this type of molecules with virtually no solubility at the physiological pH of 7.4, slight solubility is seen at pH 1 with gentle warming. For research purposes this molecule should be solubilize in DMSO or dimethyl formamide before preparation of buffered solutions, note should be made that a maximum of 10-20 µM can be prepared in aqueous solutions. BEZ235 stability is an issue in that it is light sensitive and relatively unstable at room temperature when in solution. All DMSO solutions should be stored at -20°C prior to daily use, defrosted stock solutions should not be refrozen but discarded. An expiration date of 2 years is recommended before a repeat of purity testing.

BEZ235: Preclinical investigation

Initial screening identified BEZ6244 against a panel of xenographs and cell lines demonstrating that the dual inhibition of PI3K and mTOR2 prevented cell survival as well as the feedback loop observed with mTOR1 inhibitors via the P706K phosphorylation (12). In purified PI3K isoforms was determined to have a pan-PI3K inhibition with similar BEZ235 IC50 for the alpha, gamma and delta (5.33 ± 2 nM) isoforms but demonstrating less sensitivity for the beta isoforms (IC50 – 75 nM) (5, 6, 13). Further activity against malignant melanoma (14), breast cancer (wild type and mutated) (15, 16), NSCLC (wild type and KRAS mutated) (17, 18) and human glioma’s (11). In addition BEZ235 has been investigated in conjunction with gemcitabine in pancreatic cancer showing an enhanced efficacy (19) and having the ability to overcome resistance in breast cancer to ErbB inhibitors (20). In NSCLC a combination with RAD001 (better known as rapamycin), a MTOR1 inhibitor, demonstrated synergistic activity; closer examination using NMR demonstrated deceases in the vascular structure of the tumor during treatment with this combination (21-25). A combination with the 2^nd generation mTOR1 inhibitor temsirolimus demonstrated similar results indicating that the triple inhibition of PI3K and mTOR 1&2 is more effective that single therapy of either molecule (26). In addition, BEZ235 is active in the more common forms of lymphoma such a follicular lymphoma or primary effusion lymphoma representing a novel treatment profile for these diseases. In vitro investigation has demonstrate the potent and wide ranging effects of the BEZ235 inhibitor and clinical investigations have been quickly initiated.

BEZ235: - Clinical status

BEZ235 clinical trials have been launched in response to preclinical work; which has been published in 2010 and 2011. Therefore, these trials are recruiting but no reports or data is currently available. Clinical trials initiated in breast cancer cover the wild type form of tumors and in tumors exhibiting mutated BRaf, KRAS, EGFR- and hormonal receptor positive.

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