PI3K

Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that catalyze the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) to generate the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P₃). The production of PI(3,4,5)P₃ facilitates the recruitment and activation of pleckstrin homology (PH) domain–containing proteins at the plasma membrane, thereby initiating downstream signaling cascades essential for cellular proliferation, survival, and migration.

PI3Ks are divided into three major classes, among which Class I PI3Ks are most prominently implicated in cancer biology. Class I enzymes comprise four distinct catalytic isoforms: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ.

Class IA PI3Ks, the subclass most commonly associated with oncogenic signaling, function as heterodimeric lipid kinases composed of a catalytic p110 subunit (p110α, p110β, or p110δ, encoded by PIK3CA, PIK3CB, and PIK3CD, respectively) and a regulatory p85 subunit.

The PI3K signaling pathway plays a central role in diverse biological processes, including cell cycle progression, cellular growth, survival, actin cytoskeletal rearrangement, migration, and intracellular vesicular trafficking.

Frequently Asked Questions
What is PI3K?
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate phosphatidylinositol lipids to regulate cell growth, survival, metabolism, and immune signaling. PI3K activation leads to downstream AKT and mTOR pathway signaling. Aberrant PI3K signaling is frequently observed in cancer due to PIK3CA mutations, PTEN loss, or receptor tyrosine kinase activation.
What are the different PI3K isoforms?
Class I PI3Ks include four catalytic isoforms: PI3Kα (PIK3CA) PI3Kβ (PIK3CB) PI3Kδ (PIK3CD) PI3Kγ (PIK3CG) PI3Kα and β are broadly expressed, while PI3Kδ and γ are enriched in leukocytes and play critical roles in immune regulation. Isoform selectivity is an important consideration in drug development due to toxicity and immune effects.
What are the major types of PI3K inhibitors?
PI3K inhibitors can be classified as: Pan-PI3K inhibitors Isoform-selective inhibitors (α, β, δ, γ) Dual PI3K/mTOR inhibitors Irreversible inhibitors Selectivity influences therapeutic window and toxicity profile.
How do PI3K inhibitors differ from mTOR inhibitors?
While PI3K inhibitors block upstream lipid kinase activity, mTOR inhibitors act downstream at the level of mTORC1 or mTORC2. Dual PI3K/mTOR inhibitors target both nodes of the pathway and may achieve broader pathway suppression.

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Citations
  1. Autophagy Inhibitor

    Vps34-PIK-III (PIK-III) is a selective inhibitor of VPS34 enzymatic activity.

  2. Vps34 Inhibitor

    Vps34-IN1 is a potent and highly selective Vps34 inhibitor with IC50 of 25 nM invitro,which does not significantly inhibit the isoforms of class I as well as class II PI3Ks.
  3. PI3Kδ inhibitor

    AMG319 is a potent and selective PI3Kδ inhibitor with IC50 of 18 nM, >47-fold selectivity over other PI3Ks. Phase 2.
  4. PI3K inhibitor

    PQR309 is an orally bioavailable pan inhibitor of phosphoinositide-3-kinases (PI3K) and inhibitor of the mammalian target of rapamycin (mTOR), with potential antineoplastic activity.
  5. dual PI3K and BCR-ABL inhibitor

    ON 146040 is the first dual PI3K and BCR-ABL inhibitor that targets the STAT3 and STAT5 pathways; inhibits PI3K α/δ isoforms with IC50 of 14/20 nM.
  6. PI4KIIIβ inhibitor

    PI4KIIIbeta-IN-9 is a potent PI4KIIIbeta inhibitor (IC50 of 7 nM) and is >140-fold selective over PI3Kgamma and >20-fold selective over PI3Kδ, and shows no inhibition of vps34 at concentrations up to 20 uM.
  7. PI3K α/δ inhibitor

    ETP-46321 is a potent and orally bioavailable PI3K α/δ inhibitor with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing.
  8. PI3K inhibitor

    GDC-0084 is a phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity.
  9. PI3K inhibitor

    NVP-QAV-572 is a potent PI3K kianse inhibitor with IC50 of 10 nM.
  10. PI3Kα inhibitor

    PI3Kα inhibitor 1 is a PI3Kα inhibitor extracted from patent US/20120088764A1, compound 243, has an IC50 < 0.1 uM, PI3Kα inhibitor 1 also inhibits HDAC (0.1 uM ??? IC50 ??? 1 uM) .
  11. PI3Kγ inhibitor

    PI3Kγ inhibitor 1 is a potent PI3Kγ inhibitor.
  12. PI3K/mTOR dual inhibitor

    SAR245409 is a PI3K/mTOR dual kinase inhibitor XL765 is an orally bioavailable small molecule targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) kinases in the PI3K/mTOR signaling pathway, with potential antineoplastic activity.
  13. PI3Kδ inhibitor

    TGR-1202 is an orally available, next generation PI3Kδ inhibitor, inhibits PI3Kδ activity in enzyme and cell based assays with IC50 and EC50 values of 22.2 and 24.3 nM respectively.
  14. PI3Kδ inhibitor

    TGR-1202 hydrochloride is an orally available, next generation PI3Kδ inhibitor, inhibits PI3Kδ activity in enzyme and cell based assays with IC50 and EC50 values of 22.2 and 24.3 nM respectively.
  15. PI3Kγ Inhibitor

    IPI-549 is a potent and selective PI3Kγ Inhibitor with IC50 of 16 nM.
  16. PI3Kδ inhibitor

    GSK2292767 is a potent and selective inhibitor of phosphatidylinositol 3-kinase δ (PI3Kδ; Ki = 79 pM). GSK2292767 is >100-fold selective for PI3Kδ over a panel of 250 kinases.
  17. PI3K inhibitor

    Leniolisib(CDZ 173) is a potent PI3Kδ selective inhibitor with biochemical IC50 values of 0.244, 0.424, 2.23 and 0.011 μM for PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, respectively.
  18. PI3K inhibitor

    Seletalisib is a novel small-molecule inhibitor of PI3Kδ with an IC50 value of 12 nM and shows significant selectivity to PI3Kδ with respect to the other class I PI3K isoforms (between 24- and 303-fold).
  19. dual PI3Kδ/γ inhibitor

    Tenalisib, also known as RP6530, is a potent and selective dual PI3Kδ/γ inhibitor that inhibited growth of B-cell lymphoma cell lines with a concomitant reduction in the downstream biomarker, pAKT.
  20. selective p110δ inhibitor

    IPI-3063 is a potent and selective p110δ inhibitor with biochemical IC50 of 2.5??1.2 nM and IC50 values for the other class I PI3K isoforms (p110α, p110β, p110γ) are at least 400-fold higher.
  21. SUMO inhibitor

    2-D08 is a cell permeable, mechanistically unique inhibitor of protein sumoylation. It is also inhibits Axl, IRAK4, ROS1, MLK4, GSK3β, RET, KDR and PI3Kα with IC50 values of 0.49, 3.9, 5.3, 9.8, 11, 11, 17 and 35 nM respectively in biochemical assays.
  22. PI3Kβ inhibitor

    SAR260301 is potent and selective Class I phosphatidylinositol-3-kinase (PI3K)β specific inhibitor with an IC50 of 52 nM for this isoform.
  23. Vps34 inhibitor

    Vps34-IN-2 is a novel, potent and selective inhibitor of Vps34 with IC50s of 2 and 82 nM on the Vps34 enzymatic assay and the GFP-FYVE cellular assay, respectively.
  24. PI3Kδ inhibitor

    PI3Kδ-IN-1 is a potent, selective, and efficacious PI3Kδ inhibitor with an IC50 of 1.7 nM.
  25. PI3Kγ inhibitor

    PI3Kγ inhibitor 2 (Compound 16) is an orally bioavailable, CNS-penetrant, isoform selective PI3Kγ inhibitor with a Ki of 4 nM.
  26. dual pan-PI3K/mTOR inhibitor

    PI3K/mTOR Inhibitor-2 is a potent dual pan-PI3K/mTOR inhibitor with IC50s of 3.4/34/16/1 nM for PI3Kα/PI3Kβ/PI3Kδ/PI3Kγ and 4.7 nM for mTOR. Antitumor activity.
  27. PI3Kδ/PI3Kγ inhibitor

    Tenalisib R Enantiomer is an R enantiomer of Tenalisib.
  28. PI3Kδ inhibitor

    CHMFL-PI3KD-317 is a highly potent, selective and orally active PI3Kδ inhibitor, with an IC50 of 6 nM.
  29. PI3K/mTOR inhibitor

    PI3K/mTOR Inhibitor-1 is a potent, orally bioavailable dual PI3K/mTOR inhibitor with IC50s of 20/376/204/46 nM and 186 nM for PI3Kα/PI3Kβ/PI3Kγ/PI3Kδ and mTOR, respectively. Antitumor activity.
  30. Lysosomotropic autophagy inhibitor

    IITZ-01 is a potent lysosomotropic autophagy inhibitor with single-agent antitumor activity, with an IC50 of 2.62 μM for PI3Kγ.
  31. radioprotectant

    Recilisib is a radioprotectant, which can activate AKT, PI3K activities in cells.
  32. PI3Kδ inhibitor

    Linperlisib is a potent and selective inhibitor of PI3Kδ extracted from patent WO 2015055071 A1, compound 10; has an IC50 of 6.4 nM.
  33. PI3K/mTOR inhibitor

    NSC781406 is a highly potent PI3K and mTOR inhibitor with an IC50 of 2 nM for PI3Kα.
  34. PI3Kα inhibitor

    GDC-0326 is a potent and selective PI3Kα inhibitor with a Ki of 0.2 nM.
  35. alpha-Bisabolol is a nontoxic sesquiterpene alcohol present in natural essential oil, with anticancer activity. alpha-Bisabolol exerts selective anticancer effect on A549 NSCLC cells (IC50=15 μM) via induction of cell cycle arrest, mitochondrial apoptosis and inhibition of PI3K/Akt signalling pathways. alpha-Bisabolol also strongly induces apoptosis in glioma cells.
  36. PI3Kγ inhibitor

    PI3Kγ inhibitor 3 is a potent and remarkably selective PI3Kγ inhibitor with pIC50s of 9.1, 5.1, <4.5, and 6.5 for PI3Kγ, PI3Kα, PI3Kβ, and PI3Kδ, respectively.
  37. dual pan-PI3K/mTORC1/2 inhibitor

    PQR-530 is a potent, oral and brain-penetrant dual pan-PI3K/mTORC1/2 inhibitor, exhibiting antitumor activity.
  38. PI3Kδ inhibitor

    PI3Kdelta inhibitor 1 (Compound 5d) is a potent, selective and orally available PI3Kδ inhibitor with an IC50 of 1.3 nM.
  39. PI3Kα inhibitor

    GDC-0077 (RG6114) is a potent, orally available, and selective PI3Kα inhibitor (IC50=0.038 nM).
  40. PI3K inhibitor

    CAL-130 is a novel phosphoinositide 3-kinase (PI3K) inhibitor. It is reported that combined inhibition of PI3Kδ/γ as therapy for T cell acute lymphoblastic leukemia (T-ALL).
  41. PI3K inhibitor

    CAL-130 Hydrochloride is a novel phosphoinositide 3-kinase (PI3K) inhibitor. It is reported that combined inhibition of PI3Kδ/γ as therapy for T cell acute lymphoblastic leukemia (T-ALL).
  42. PI3K inhibitor

    LY303511, an inactive analogue of LY294002, is a mTOR inhibitor that did not inhibit PI3-K.
  43. PI3K Inhibitor

    NVP-BKM120 Hydrochloride is a selective PI3K inhibitor of p110α/β/δ/γ with IC50 of 52 nM/166 nM/116 nM/262 nM, respectively. Reduced potency against VPS34, mTOR, DNA-PK, with little activity to PI4Kβ.
  44. PI3K Inhibitor

    PI103 is a potent inhibitor with low IC50 values against recombinant PI3K isoforms p110alpha (IC50= 2 nM), p110beta (IC50= 3 nM), p110delta (IC50= 3 nM), and p110gamma (IC50= 15 nM), less potent to mTOR/DNA-PK with IC50 of 30 nM/23 nM.
  45. PI3K Inhibitor

    XL147 is a potent, orally bioavailable inhibitor of the class I PI3K family of lipid kinases.
  46. p110α inhibitor

    MLN1117, also known as INK1117 and TAK-117, is an orally bioavailable inhibitor of the class I phosphoinositide 3-kinase (PI3K) alpha isoform with potential antineoplastic activity.
  47. endothelial barrier enhancer

    Ginsenoside Rk1, one of the main elements of Sung Ginseng, has been confirmed as a new endothelial barrier enhancer recently and has anti-cancer activity.
  48. PI3K inhibitor

    AZD8186 is an isoform-specific small-molecule PI3K inhibitor, potently inhibits PI3Kβ (IC50=4 nM) and PI3Kδ (IC50=12 nM) with selectivity over PI3Kα (IC50=35 nM) and PI3Kγ (IC50=675 nM).
  49. 4-Methylbenzylidene camphor(4-MBC; Enzacamene)is an organic camphor derivative that is used in the cosmetic industry for its ability to protect the skin against UV, specifically UV B radiation.
  50. EGFR/PI3K dual inhibitor

    MTX-211 is a dual inhibitor of EGFR and PI3K, which plays important roles in the progression of KRAS mutant colorectal cancer. MTX-211 has the potential for the treatment of KRAS mutant colorectal cancer.

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