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Protein / target

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform

Encoded byPIK3CAP42336Homo sapiensSwiss-Prot
Clinically validated
Therapeutic maturity
4
Approved medicines
Open Targets target-level
View by indication →
30
Clinical trials
Small-molecule tractable
Druggability
Approved Drug

Protein at a glance

Biological role

1-phosphatidylinositol-4,5-bisphosphate 3-kinase

Strongest disease association

Megalencephaly-capillary malformation-polymicrogyria syndrome

Via encoding gene PIK3CA · Genetic evidence · score 0.96

Therapeutic position

Established drug target

Small molecules

Derived from structured UniProt, Open Targets and literature data on this page.

Protein profile

UniProt 2026_02

Canonical identity and biological annotation from UniProt.

Function overview

Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

View complete UniProt function annotation

Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396, PubMed:28676499). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. In addition to its lipid kinase activity, it displays a serine-protein kinase activity that results in the autophosphorylation of the p85alpha regulatory subunit as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others (PubMed:23936502, PubMed:28676499). Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity)

Domains and Gene Ontology detail (62)

Domains & features

PI3K-ABDPI3K-RBDC2 PI3K-typePIK helicalPI3K/PI4K catalytic

Gene Ontology

  • Ccytoplasm
  • Ccytosol
  • Cintercalated disc
  • Clamellipodium
  • Cperinuclear region of cytoplasm
  • Cphosphatidylinositol 3-kinase complex
  • Cphosphatidylinositol 3-kinase complex, class IA
  • Cphosphatidylinositol 3-kinase complex, class IB
  • Cplasma membrane
  • F1-phosphatidylinositol-3-kinase activity
  • F1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
  • F1-phosphatidylinositol-4-phosphate 3-kinase activity

1068 aa · 124 kDa

Biological roles

Reactome v97

What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.

Receptor tyrosine kinase signallingUniProt · ReactomeCell migrationUniProt · GOGrowth-factor signallingGOCell proliferation & survivalReactomeOncogenic signallingReactomeImmune signallingGO · Reactome
View supporting evidence

Receptor tyrosine kinase signalling

  • ·Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosph…
  • ·PI3K events in ERBB4 signaling
  • ·PI3K events in ERBB2 signaling

Cell migration

  • ·Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosph…
  • ·cell migration
  • ·endothelial cell migration

Growth-factor signalling

  • ·epidermal growth factor receptor signaling pathway
  • ·insulin-like growth factor receptor signaling pathway

Cell proliferation & survival

  • ·PIP3 activates AKT signaling
  • ·CD28 dependent PI3K/Akt signaling

Oncogenic signalling

  • ·Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
  • ·Constitutive Signaling by Aberrant PI3K in Cancer

Immune signalling

  • ·T cell receptor signaling pathway
  • ·Interleukin-3, Interleukin-5 and GM-CSF signaling
View underlying pathways (25)

Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.

Interaction neighbourhood

STRING v12.0

Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.

PIK3R5PIK3R2IRS1EGFRPIK3R3PIK3R1PIK3CDPIK3CBAKT1KRASPIK3CA

10 strongest partners — larger node and heavier line mean higher confidence

Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.

Approved medicines with mapped indications

3 medicines · 2 areas

Approved therapies targeting this protein, grouped by what they are approved to treat — the disease-first view of the medicines below. Relationships come from the canonical approved-indication graph (ChEMBL phase-4), the same source as the drug cards.

Breast Neoplasms2 medicines
Neoplasms2 medicines

4 medicines meet Open Targets' target-level approved-medicine definition; the 3 shown here are those on this page with a canonical approved disease indication in the graph. Approved indications from ChEMBL (phase-4), via the canonical drug→disease graph.

Drugs targeting this protein

3

How approved and investigational drugs engage this protein — mechanism and action type, direct vs complex targeting, and how broadly each acts across other targets. A drug-first view (the section above groups the approved ones disease-first); direct binders with few recorded targets are listed first.

Alpelisib
Narrow target profileApprovedInhibitor

PI3-kinase p110-alpha subunit inhibitor

Indicated for Breast Neoplasms, Neoplasms

Direct interaction with this protein · Only this protein recorded as a target

inavolisib
Narrow target profileApprovedInhibitor

PI3-kinase p110-alpha subunit inhibitor

Indicated for Breast Neoplasms

Direct interaction with this protein · Only this protein recorded as a target

copanlisib
Narrow target profileApprovedInhibitor

PI3-kinase p110-alpha subunit inhibitor

Indicated for Neoplasms

Direct interaction with this protein · 1 of 2 recorded protein targets — narrow recorded profile

ChEMBL mechanism, action type, target identity and approved indications. Open Targets clinical status.

Translational evidence

Open Targets 26

Why this target matters therapeutically, strongest evidence first. Disease associations are gene-level (via the gene that encodes this protein) and open into the full confidence synthesis; the development universe, tractability and safety annotations are target-level, from Open Targets.

Strongest disease associations · via encoding gene PIK3CA

Gene-level evidence surfaced through the gene PIK3CAthat encodes this protein — not a direct protein–disease relationship. Ranked by Forefront's causal-directness weighting, so genetically- and clinically-evidenced diseases lead over ones that merely share the literature.

Megalencephaly-capillary malformation-polymicrogyria syndrome
0.99Well supported

Genetic evidence dominant · Open Targets 0.85

Breast Neoplasms
0.98Well supported

Genetic evidence dominant · Open Targets 0.75

PIK3CA-related overgrowth spectrum
0.97Well supported

Genetic evidence dominant · Open Targets 0.77

CLOVE syndrome
0.95Well supported

Genetic evidence dominant · Open Targets 0.80

CLOVES syndrome
0.95Well supported

Genetic evidence dominant · Open Targets 0.79

View evidence synthesis (5)
Megalencephaly-capillary malformation-polymicrogyria syndromeWell supported
0.99
agreement 0.891.00
Genetic58%Somatic mutation35%Clinical6%Literature2%Genetic literaturedup

Open Targets aggregate 0.85 · 4 independent evidence families · 1 not counted as duplicate

Breast NeoplasmsWell supported
0.98
agreement 0.871.00
Genetic52%Clinical40%Literature9%Genetic literaturedup

Open Targets aggregate 0.75 · 3 independent evidence families · 1 not counted as duplicate

PIK3CA-related overgrowth spectrumWell supported
0.97
agreement 0.881.00
Genetic55%Somatic mutation37%Clinical8%Literature0%Genetic literaturedup

Open Targets aggregate 0.77 · 4 independent evidence families · 1 not counted as duplicate

CLOVE syndromeWell supported
0.95
agreement 0.841.00
Genetic58%Somatic mutation38%Literature4%Genetic literaturedup

Open Targets aggregate 0.80 · 3 independent evidence families · 1 not counted as duplicate

CLOVES syndromeWell supported
0.95
agreement 0.841.00
Genetic58%Somatic mutation38%Literature4%Genetic literaturedup

Open Targets aggregate 0.79 · 3 independent evidence families · 1 not counted as duplicate

The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the per-type scores above show the calculation.

Show all associations
Megalencephaly-capillary malformation-polymicrogyria syndrome0.85
CLOVE syndrome0.80
CLOVES syndrome0.79
PIK3CA-related overgrowth spectrum0.77
Breast Neoplasms0.75
Cowden syndrome 50.75
Ovarian Neoplasms0.73
Seborrheic keratosis0.73
Breast adenocarcinoma0.73
CLAPO syndrome0.72

Drug development

32 compounds recorded · 4 approved · 27 in clinical development · 1 earlier-stage

Open Targets' development universe — every compound recorded against the target at any stage, not all approved medicines. Distinct from the 3 drugs that target this protein in Forefront's canonical graph (3 with a mapped approved indication, shown above): these count different sets and are not a subset relation.

View all recorded compounds (10)
PANULISIBPhase 1
PILARALISIBPhase 2
IZORLISIBPhase 1 2
SF-1126Phase 2
COPANLISIBApproval
PKI-179Phase 1
RECILISIBPhase 1
PICTILISIBPhase 2
DACTOLISIBPhase 3
SAMOTOLISIBPhase 2

Open Targets known-drugs universe. Drug name and highest clinical stage only — the disease relationship is NOT read from this slice (it carries trial-context noise); approved indications come from the canonical graph above.

Tractability

Small moleculesStrong

Approved Drug and Structure with Ligand support this modality.

AntibodiesEmerging

Feasibility evidence (go cc med conf) — no clinical-stage drug of this modality recorded.

Protein degradersEmerging

Feasibility evidence (literature and database ubiquitination) — no clinical-stage drug of this modality recorded.

View underlying tractability evidence (10)
SM · Approved DrugSM · Structure with LigandSM · High-Quality LigandSM · High-Quality PocketSM · Druggable FamilyAB · GO CC med confPR · LiteraturePR · Database UbiquitinationPR · Half-life DataPR · Small Molecule Binder

Raw Open Targets tractability assessment buckets, by modality.

Safety-related annotations

regulation of catalytic activityToxCastdrug toxicityClinPGxNo significant resultsClinPGxheart diseaseForce et al. (2011)

Terms indexed against this target in Open Targets' safety data, with their datasource. These are annotations, not causal claims: the direction of effect (whether activation or inhibition is implicated), species and evidence strength are not captured here, so an entry does not mean that modulating this target is known to cause that condition.

Clinical trials

30

Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein. Ranked by active status, then clinical phase and recency, and spread across the targeting drugs.

View all trials (26)

RECRUITING · via Alpelisib · NCT05564377

ClinicalTrials.gov via the drug-target graph.

What's happening now

10

Recent therapeutic activity around this target — regulatory actions, clinical trials and safety signals for 2 drugs that target this protein, plus publications where such a drug is a genuine subject. Every item is reached indirectly through the drug, not the protein itself; incidental mentions (a paper that merely measures a drug) and press items are excluded.

  1. Regulatory approval2026-07-15

    Approval: Vijoice (EMA)

    ema · regulatory · ema · via Alpelisib

  2. CHMP positive opinion2026-05-22

    CHMP positive opinion: Vijoice (EMA)

    ema · regulatory · ema · via Alpelisib

  3. Label change2025-07-22

    Label change: ALPELISIB (NDA215039)

    fda · regulatory · fda · via Alpelisib

  4. Regulatory approval2025-07-18

    Approval: Itovebi (EMA)

    ema · regulatory · ema · via inavolisib

  5. Indication expanded2024-04-24

    Indication expansion: ALPELISIB (NDA215039)

    fda · regulatory · fda · via Alpelisib

  6. Label change2022-11-17

    Label change: ALPELISIB (NDA215039)

    fda · regulatory · fda · via Alpelisib

  7. Regulatory approval2022-04-05

    Approval: ALPELISIB (NDA215039)

    fda · regulatory · fda · via Alpelisib

  8. New publication2020-11-25
    Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1.

    Annals of oncology : official journal of the European Society for Medical Oncology · 2021 · 447 citations · Europe PMC · via Alpelisib

  9. Regulatory approval2020-07-27

    Approval: Piqray (EMA)

    ema · regulatory · ema · via Alpelisib

  10. New publication2019-05-01
    Alpelisib for <i>PIK3CA</i>-Mutated, Hormone Receptor-Positive Advanced Breast Cancer.

    The New England journal of medicine · 2019 · 1,948 citations · Europe PMC · via Alpelisib

Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.

Related family literature

1

Papers about “Class Ia Phosphatidylinositol 3-Kinase” — a broader family this protein belongs to. Shown as context; not counted as papers specifically about this protein.

The Role of PIK3R1 in Metabolic Function and Insulin Sensitivity.

Tsay A · International journal of molecular sciences · 2023

via Class Ia Phosphatidylinositol 3-Kinase

Europe PMC literature, reached through curated HGNC family membership. Membership is a taxonomic relationship — it does not imply this protein participates in every mechanism these papers discuss.