PI3K (Phosphoinositide 3-kinase), via phosphorylation of the inositol lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), forms the second messenger molecule phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) which recruits and activates pleckstrin homology domain containing proteins, leading to downstream signalling events crucial for proliferation, survival and migration. Class I PI3K enzymes consist of four distinct catalytic isoforms, PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ.
There are three major classes of PI3K enzymes, being class IA widely associated to cancer. Class IA PI3K are heterodimeric lipid kinases composed of a catalytic subunit (p110α, p110β, or p110δ; encoded by PIK3CA, PIK3CB, and PIK3CD genes, respectively) and a regulatory subunit (p85).
The PI3K pathway plays an important role in many biological processes, including cell cycle progression, cell growth, survival, actin rearrangement and migration, and intracellular vesicular transport.
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GDC-0077 (RG-6114) is a potent, highly isoform selective inhibitor of PI3Kα, with IC50 of 0.038 nM, >300-fold selective over β, δ, and γ isoforms, as well as PIKK-family proteins such as mTOR, DNA-PK and VPS34; induces depletion of mutant PI3K alpha protein resulting in reduction of PI3K pathway biomarkers such as pAkt and pPRAS40, inhibition of cell proliferation and increased apoptosis in human PIK3CA mutant breast cancer cell lines to a greater extent when compared to PIK3CA wild-type cells; causes tumor regressions in cell-culture-derived and patient derived PIK3CA mutant breast cancer xenograft models.
A first-in-class, highly selective, dual inhibitor of PI3K and EGFR kinases with demonstrated in vivo anticancer activity against multiple KRAS mutant colorectal tumors; shows limited off-target toxicity and a broad therapeutic window.
IPI-549 (IPI549) is a potent, highly selective, orally active inhibitor of PI3Kγ with IC50 of 16 nM, displays >100-fold selectivity over other lipid and protein kinases (PI3Kα IC50=3.2 uM, PI3Kβ IC50=3.5 uM, PI3Kδ IC50>8.4 uM); demonstrates excellent PI3Kγ potency (IC50=1.2 nM) and selectivity against other Class I PI3K isoforms (>146-fold) in cellular phospho-AKT assays, dose dependently inhibits PI3Kγ dependent bone marrow-derived macrophage (BMDM) migration; demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo.
Autophinib is a novel, potent autophagy inhibitor that inhibits autophagy induced by starvation (IC50=90 nM) or rapamycin (IC50=40 nM) by targeting the lipid kinase VPS34 (IC50=19 nM); inhibits LC3 lipidation to form LC3-II, also inhibits p62 degradation dose-dependently in starved MCF7-LC3 cells; an ATP-competitive inhibitor of VPS34 but not other lipid kinases, mTOR and TBK1.
A potent, selective, orally active p110δ/γ PI3K dual inhibitor with IC50 of 24.5 and 33.2 nM, respectively; displays good selectivity over p110α (>300-fold) and p110β (>100-fold) isoforms; inhibits LPS induced CD19+ cell proliferation in human whole blood with EC50 of 250 nM, and LPS induced CD45R+ cell proliferation in mouse whole blood with EC50 of 101 nM; shows the potential for treatment of cancer and inflammation diseases.
TGR-1202 (RP5264,TGR1202,Umbralisib) is a potent, selective, orally available PI3Kδ inhibitor with IC50 of 22 nM, 50-fold selectivity over PI3Kα/β and >10,000 fold over PI3Kγ; enhances Brentuximab Vedotin-induced Hodgkin lymphoma cell death via mitotic arrest, demonstrates highly synergistic effect with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells; synergistically disrupts the 4E-BP1-eIF4F-c-Myc axis with carfilzomib, also potently inhibits 60% of the activity of CK1ε at 1uM.
TGR-1202 R-enantiomer is is the less active enantiomer of TGR-1202 (Umbralisib), TGR-1202 is a potent, selective, orally available PI3Kδ inhibitor with IC50 of 22 nM.
Umbralisib (RP5264,TGR1202, TGR-1202) is a potent, selective, orally available PI3Kδ inhibitor with IC50 of 22 nM, 50-fold selectivity over PI3Kα/β and >10,000 fold over PI3Kγ; enhances Brentuximab Vedotin-induced Hodgkin lymphoma cell death via mitotic arrest, demonstrates highly synergistic effect with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells; synergistically disrupts the 4E-BP1-eIF4F-c-Myc axis with carfilzomib, also potently inhibits 60% of the activity of CK1ε at 1 uM.
SAR405 is a highly potent and selective PI3K class III isoform Vps34 inhibitor with IC50 of 1.2 nM, inhibits the formation of autophagosomes in GFP-LC3 cells with IC50 of 4 nM; displays no activity against class I and II PI3K isoforms (IC50>10 uM), as well as PIKKs, ATM, ATR and DNA-PK, SMG1; affects both late endosome-lysosome compartments and prevents autophagy, shows synergistic antiproliferative activity in renal tumor cell lines combined with mTOR inhibitor everolimus; enhances the antitumor efficacy of cisplatin in mouse xenograft model of HNSCC.
ON 146040 is a potent, dual PI3K/BCR-ABL inhibitor with IC50 of 14/20 nM for PI3Kα/δ , IC50 of 20 nM for BCR/ABL; displaysno significant effect on PI3Kβ/γ isoforms (IC50=3/1 uM), also inhibits Abl1 and several mutant versions of Abl (IC50<150 nM) but not the T315I mutant; abrogates the oncogenic signaling of STAT3 and STAT5, ON 146040 is highly potent in killing hematologic tumor cells with IC50 values of 150-1,000 nM, down-regulates STAT3 and STAT5 phosphorylation in leukemia and myeloma cells.
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