Phosphoinositide 3-kinase inhibitor

A Phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a potential medical drug that functions by inhibiting a Phosphoinositide 3-kinase enzyme which is part of the PI3K/AKT/mTOR pathway, which plays a key role in cancer. Inhibiting this pathway often suppresses tumor growth.

There are a number of different classes and isoforms of PI3Ks. Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) - p110 alpha, p110 beta, p110 gamma and p110 delta. The inhibitors being studied inhibit one or more isoforms of the class I PI3Ks.

They are being actively investigated for treatment of various cancers.

They are also being considered for Inflammatory respiratory disease.

Notable examples

 * Wortmannin an irreversible inhibitor of PI3K.
 * demethoxyviridin a derivative of wortmannin.
 * LY294002 a reversible inhibitor of PI3K.

Late stage
In phase III clinical trials:
 * Perifosine, for colorectal cancer and multiple myeloma.

In phase II clinical trials:
 * CAL101 oral, p110δ(delta) selective with good clinical results, eg. in leukemias. Starting a phase II trial
 * PX-866  Starting 4 phase II trials.

Early stage
In early stage clinical trials
 * BEZ235 The first into clinical trials, in 2006. A PI3K/mTOR dual inhibitor.
 * SF1126  Some early clinical data has been presented.   First PI3KI 'Orphan Drug' (for B-cell chronic lymphocytic leukemia (CLL).
 * GDC-0941    IC50 of 3nM.
 * BKM120
 * XL147
 * XL765
 * Palomid 529
 * GSK615
 * ZSTK474, a potent inhibitor against p110a.
 * PWT33597, a dual PI3K-alpha/mTOR inhibitor - for advanced solid tumors. IND mid 2011. Phase I recruiting.

Others
 * IC87114 a selective inhibitor of p110δ. It has an IC50 of 100 nM for inhibition of p110-δ.
 * TG100–115, inhibits all four isoforms but has a 5-10 fold better potency against p110-γ and p110-δ.
 * CAL263
 * PI-103 Dual PI3K-mTOR inhibitor.
 * SAR245408, SAR245409
 * GNE-477 is PI3K-alpha and mTOR inhibitor with IC50 values of 4nM and 21nM.
 * CUDC-907, Also an HDAC inhibitor.