Phosphoinositide 3-kinase inhibitor
Encyclopedia
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 PI3K
s. Class 1 PI3K
s 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.
In/starting phase II clinical trials:
Others
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
enzyme which is part of the PI3K/AKT/mTOR pathway
PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signalling pathway important in apoptosis and hence cancer e.g. breast cancerand non-small-cell lung cancer.]PI3K activation activates AKT which activates mTOR....
, which plays a key role in cancer. Inhibiting this pathway often suppresses tumor growth.
There are a number of different classes and isoforms of PI3K
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
s. Class 1 PI3K
Class I PI 3-kinases
Class I PI 3-kinases are a subgroup of the enzyme family, phosphoinositide 3-kinase that possess a common protein domain structure, substrate specificity, and method of activation...
s have a catalytic subunit known as p110, with four types (isoforms) - p110 alpha, p110 beta
PIK3CB
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta isoform is an enzyme that in humans is encoded by the PIK3CB gene.-Further reading:...
, p110 gamma
PIK3CG
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform is an enzyme that in humans is encoded by the PIK3CG gene.-Interactions:PIK3CG has been shown to interact with PIK3CD, KRAS, PIK3R5 and BCR gene.-Further reading:...
and p110 delta
P110δ
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase or p110δ is an enzyme that in humans is encoded by the PIK3CD gene....
. 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
- WortmanninWortmanninWortmannin, a furanosteroid metabolite of the fungi Penicillium funiculosum, Talaromyces wortmannii,is a specific, covalent inhibitor of phosphoinositide 3-kinases . It has an in vitro inhibitory concentration of around 5 nM, making it a more potent inhibitor than LY294002, another commonly...
an irreversible inhibitor of PI3K. - demethoxyviridin a derivative of wortmannin.
- LY294002LY294002LY294002 is a morpholine derivative of quercetin. It is a potent inhibitor of phosphoinositide 3-kinases . Two of these are the proto-oncogene serine/threonine-protein kinase and the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform...
a reversible inhibitor of PI3K.
Late stage
In phase III clinical trials:- PerifosinePerifosinePerifosine is a drug candidate being developed for a variety of cancer indications.It is an alkylphospholipid Perifosine is structurally related to miltefosine...
, for colorectal cancerColorectal cancerColorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
and multiple myelomaMultiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
.
In/starting phase II clinical trials:
- CAL101 an oral PI3K delta with promising early Phase I results in certain late-stage types of leukemiaLeukemiaLeukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
s. Starting a phase II trial - PX-866 Starting 4 phase II trials.
Early stage
In early stage clinical trials- BEZ235BEZ235BEZ235 or NVP-BEZ235 is an imidazoquinoline derivative and PI3K inhibitor being investigated as a possible cancer treatment.It has been shown to be toxic to Waldenström's macroglobulinemia cells....
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 leukemiaChronic lymphocytic leukemiaB-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
(CLL). - INK1117, a PI3K-alpha inhibitor in phase I.
- IPI-145, a novel inhibitor of PI3K delta and gamma,especially for hematologic malignancies (currently in two Phase 1 clinical trials in hematologic cancers as well as a broad range of inflammatory conditions).
- 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 p110δP110δPhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase or p110δ is an enzyme that in humans is encoded by the PIK3CD gene....
. It has an IC50IC50The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...
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.