AKT1 AKT serine/threonine kinase 1
ENSG00000142208 · protein coding · Open Targets profile
AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:11882383, PubMed:15526160, PubMed:15861136, PubMed:21432781, PubMed:21620960, PubMed:31204173). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:11882383, PubMed:15526160, PubMed:21432781, PubMed:21620960, PubMed:29343641, PubMed:31204173). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:11882383, PubMed:15526160, PubMed:21432781, PubMed:21620960). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT also regulates the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT also regulates cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the mTORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915, PubMed:12172553). Also regulates the mTORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 and DEPDC5 (PubMed:31548394, PubMed:33594058). AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Part of a positive feedback loop of mTORC2 signaling by mediating phosphorylation of MAPKAP1/SIN1, promoting mTORC2 activation (By similarity). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor 1 (IGF1) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF1 (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (PubMed:32322062). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865). Acts as a regulator of mitochondrial calcium uptake by mediating phosphorylation of MICU1 in the mitochondrial intermembrane space, impairing MICU1 maturation (PubMed:30504268). Acts as an inhibitor of tRNA methylation by mediating phosphorylation of the N-terminus of METTL1, thereby inhibiting METTL1 methyltransferase activity (PubMed:15861136). In response to LPAR1 receptor pathway activation, phosphorylates Rabin8/RAB3IP which alters its activity and phosphorylates WDR44 which induces WDR44 binding to Rab11, thereby switching Rab11 vesicular function from preciliary trafficking to endocytic recycling (PubMed:31204173). {ECO:0000250|UniProtKB:P31750, ECO:0000250|UniProtKB:P47196, ECO:0000269|PubMed:10358075, ECO:0000269|PubMed:10576742, ECO:0000269|PubMed:10926925, ECO:0000269|PubMed:11154276, ECO:0000269|PubMed:11994271, ECO:0000269|PubMed:12150915, ECO:0000269|PubMed:12172553, ECO:0000269|PubMed:12176338, ECO:0000269|PubMed:12964941, ECO:0000269|PubMed:15861136, ECO:0000269|PubMed:16139227, ECO:0000269|PubMed:16982699, ECO:0000269|PubMed:17726016, ECO:0000269|PubMed:18507042, ECO:0000269|PubMed:19592491, ECO:0000269|PubMed:19934221, ECO:0000269|PubMed:20086174, ECO:0000269|PubMed:20471940, ECO:0000269|PubMed:20682768, ECO:0000269|PubMed:23431171, ECO:0000269|PubMed:30504268, ECO:0000269|PubMed:31204173, ECO:0000269|PubMed:31548394, ECO:0000269|PubMed:32228865, ECO:0000269|PubMed:32322062, ECO:0000269|PubMed:33594058, ECO:0000269|PubMed:9829964, ECO:0000303|PubMed:11882383, ECO:0000303|PubMed:15526160, ECO:0000303|PubMed:21432781, ECO:0000303|PubMed:21620960}.
Each band is a group of drugs. It runs from the kind of drug on the left to the furthest stage that drug has reached in any disease on the right. Thicker bands mean more drugs.
Approved bands are highlighted. Withdrawn means the drug was pulled from the market or from development. A combined phase counts as the later one (Phase 1/2 is shown as Phase 2). Hover a band for the drug names. Source: Open Targets Platform, fetched live.
Each row is a cancer, strongest overall evidence first. The two dots show how strong the inherited (germline) and tumour-mutation (somatic) evidence is; the line between them is the gap.
Scores run from 0 (no evidence) to 1 (strongest). A missing dot at 0 means Open Targets holds no evidence of that kind. Source: Open Targets Platform, fetched live.
Tractability
- Small molecule
- Advanced Clinical, Structure with Ligand, High-Quality Ligand, High-Quality Pocket, Druggable Family
- Antibody
- UniProt loc high conf, GO CC high conf
- PROTAC
- Literature, UniProt Ubiquitination, Database Ubiquitination, Half-life Data, Small Molecule Binder
gnomAD loss of function constraint: o/e 0.332720011472702 (upper bound 0.47912999987602234). Low values mean loss of function is poorly tolerated, a safety flag for inhibition.
Who runs trials of these drugs
Principal investigators and study chairs on 102 registry trials, updated in the last three years, of the most advanced drugs against AKT1 (capivasertib, afuresertib, ipatasertib, uprosertib, MK-2206, pifusertib, miransertib), ranked by Phase 2+ trials. Live from ClinicalTrials.gov.
- Peter SchmidWestdeutsche Studiengruppe GmbH · 6 of 6 trials Phase 2+Ph3NCT07281833 · Phase III Study to Evaluate the Safety, Efficacy, and Impact on Quality of Life of Capivasertib Alongside Standard-of-care Endocrine Treatment in Patients With HR+/HER2- Advanced Breast Cancer and Progression on Prior Endocrine-based Treatmentbrief
- Kevin M KalinskyECOG-ACRIN Cancer Research Group · 2 of 2 trials Phase 2+
- Aaron HansenUniversity Health Network, Toronto, ON, Canada · 1 of 1 trials Phase 2+
- Alexander N ShoushtariMemorial Sloan Kettering Cancer Center · 1 of 1 trials Phase 2+
- Alicia OkinesRoyal Marsden NHS Foundation Trust · 1 of 1 trials Phase 2+
- Andreas SchneeweissNational Center for Tumor Diseases (NCT) · 1 of 1 trials Phase 2+
- Andrej LissatCharite University, Berlin, Germany · 1 of 1 trials Phase 2+
- Anna C FerrariECOG-ACRIN Cancer Research Group · 1 of 1 trials Phase 2+
- Antoni RibasSWOG Cancer Research Network · 1 of 1 trials Phase 2+
- Antonio LlombartMedSIR · 1 of 1 trials Phase 2+
- Arun RajanNational Cancer Institute (NCI) · 1 of 1 trials Phase 2+
- Ashkan MortezaviUniversity Hospital, Basel, Switzerland · 1 of 1 trials Phase 2+
- Benoit YOUService d'Oncologie Médicale - Centre Hospitalier Lyon Sud · 1 of 1 trials Phase 2+
- Birgit GeoergerGustave Roussy, Cancer Campus, Grand Paris · 1 of 1 trials Phase 2+
- Caner SayginUniversity of Chicago · 1 of 1 trials Phase 2+
Registry trials of capivasertib, afuresertib, ipatasertib, uprosertib, MK-2206, pifusertib, miransertib updated in the last three years, counted by the country group of their listed sites. A trial with sites in several groups counts in each; 55 of 99 have all sites in one country.
Site counts are not patients per country, and trials registered only outside ClinicalTrials.gov are not covered. Where sites are is a fact about the record, not a judgement of its quality. Europe is the EU and EEA, the UK and Switzerland. 3 trials list no sites and are left out. Source: ClinicalTrials.gov, fetched live.
36 trials of drugs against AKT1 were stopped early; 7 give no reason
Terminated, withdrawn and suspended interventional trials of capivasertib, afuresertib, ipatasertib, uprosertib, MK-2206, pifusertib, miransertib, LY-2780301, triciribine, XL-418, SR-13668, TAS0612, newest update first, live from ClinicalTrials.gov. Each reason is quoted exactly as the registry gives it; we do not sort reasons into safety, efficacy or business. Dates are the last registry update. Showing the 25 most recent of 36.
- terminated · 2026-05-12 · Hoffmann-La Roche · Ipatasertib“Study was closed early as the sponsor decided not to continue development of certain treatment combinations.”
- terminated · 2026-04-21 · Institut Paoli-Calmettes · matched by the registry's drug synonyms“Drug development stopped”
- terminated · 2026-02-25 · Gordon Mills, MD, PhD · Capivasertib“loss of funding”
- withdrawn · 2025-12-24 · Imperial College London · Capivasertib“Study was stopped because funder pulled funding for the study. 2 patients were screened however none of the screen patients were eventually recruited”
- terminated · 2025-12-01 · Gustave Roussy, Cancer Campus, Grand Paris · matched by the registry's drug synonyms“Abandon of the partner, ROCHE”
- terminated · 2025-03-13 · Taiho Oncology, Inc. · TAS0612“Taiho Oncology as the sponsor of study TAS0612-101, has made a strategic decision to terminate the TAS0612-101 study, taking into consideration the safety profile of TAS0612 and the absence of encouraging anti-tumor activity.”
- terminated · 2024-11-08 · Hoffmann-La Roche · Ipatasertib“The decision to not open the Phase III portion was based on a strategic sponsor decision and not driven by any safety concerns.”
- terminated · 2024-06-04 · Merck Sharp & Dohme LLC · MK-2206No reason given
- terminated · 2023-11-13 · David VanderWeele · Ipatasertib“Funder Decision”
- terminated · 2023-10-17 · Hoffmann-La Roche · Ipatasertib“Despite many risk-minimization strategies, the combination of ipatasertib, atezolizumab and docetaxel was challenging due to multiple study treatment modifications required to manage toxicity, making further enrollment inappropriate.”
- terminated · 2023-04-13 · ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA) · Miransertib“Early termination due to business reasons”
- terminated · 2022-12-28 · Joseph Paul Eder · matched by the registry's drug synonyms“The study was paused during COVID and without the ability to initiate the 4th arm in the study, the decision was to terminate the study in 2022.”
- withdrawn · 2021-10-25 · Washington University School of Medicine · matched by the registry's drug synonyms“Study Funding no longer available”
- terminated · 2021-08-11 · Novartis Pharmaceuticals · Afuresertib“Company decision”
- withdrawn · 2020-10-06 · Icahn School of Medicine at Mount Sinai · Ipatasertib“Evolving data with Ipatasertib that changes the known risk / benefit background in pursuing future studies.”
- terminated · 2020-09-30 · ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA) · matched by the registry's drug synonymsNo reason given
- terminated · 2020-09-24 · Prescient Therapeutics, Ltd. · Triciribine“Enrollment stopped prior to Phase 1b, change in strategic focus”
- terminated · 2020-09-24 · Prescient Therapeutics, Ltd. · Triciribine Phosphate“criteria for continuing enrollment in Phase 2 portion was not met”
- terminated · 2019-10-10 · National Cancer Institute (NCI) · matched by the registry's drug synonymsNo reason given
- terminated · 2019-05-20 · Samsung Medical Center · matched by the registry's drug synonyms“lack of efficacy”
- terminated · 2018-08-16 · Merck Sharp & Dohme LLC · MK-2206“The study was terminated for business reasons and not due to any safety or efficacy concerns related to dalotuzumab.”
- terminated · 2018-05-08 · National Cancer Institute (NCI) · matched by the registry's drug synonyms“Study did not pass Stage 1 interim analysis.”
- terminated · 2017-08-30 · National Cancer Institute (NCI) · matched by the registry's drug synonyms“terminated early, due to toxicity”
- withdrawn · 2016-10-06 · GlaxoSmithKline · Afuresertib“Study cancelled: Withdrawn before enrollment of any participants”
- terminated · 2016-05-04 · Novartis · AfuresertibNo reason given
Paediatric incentives and obligations for AKT1's drugs
For capivasertib, afuresertib, ipatasertib, uprosertib, MK-2206, pifusertib, miransertib, LY-2780301, triciribine, XL-418, SR-13668, TAS0612: what EMA and FDA publish about paediatric plans, orphan status and pediatric approvals, and how many registered studies take children. Each line is a yes, no or not published fact from the record linked under it; none of it is a forecast.
- FDA pediatric target list: no · AKT1 is not on the listRule: Target is on FDA's Pediatric Molecular Target List (relevant targets). Source: FDA Pediatric Molecular Target List (Listed as February 2026 on the FDA Pediatric Oncology page; the file served is 9.7.22_the_relevant_molecular_target_list.xlsx, whose Summary of Changes sheet is headed 'SEPTEMBER 2022 UPDATE' (footnote date 2022-09-01)), 2026-11-11
- EU paediatric investigation plan: yes · EMEA-002551-PIP01-18 (capivasertib, Treatment of breast cancer;Treatment of prostate cancer): W: decision granting a waiver in all age groups for all conditions or indications, 12 Jun 2019; EMEA-002396-PIP01-18 (Ipatasertib, Treatment of breast cancer;Treatment of prostate cancer): W: decision granting a waiver in all age groups for all conditions or indications, 7 Dec 2018Rule: An EMA PIP decision (agreement, modification or waiver) lists the drug as its active substance, exact name. Source: EMA data download (dated snapshot), 2026-11-11
- EU orphan designation: yes · EU/3/18/1997 positive 21 Mar 2018: Treatment of Proteus syndromeRule: An EU orphan designation lists the drug as its active substance (exact name) or belongs to a medicine that does; withdrawn and expired designations are listed with their status. Source: EMA EU/3/18/1997, 2026-11-11
- Authorised in the EU: yes · Truqap: authorised since 17 Jun 2024Rule: An EMA medicine record lists the drug as its active substance or INN, exact name; national-only authorisations are not in this file. Source: EMA EPAR Truqap, 2026-11-11
- FDA orphan designation: not published · FDA's orphan designation database turns away automated requests, so this app does not read it; search it by hand at the linkRule: Would be: an FDA orphan designation names the drug. Source: FDA orphan designations search
- FDA pediatric oncology approval: no · FDA's table lists no pediatric approval of capivasertib, afuresertib, ipatasertib, uprosertib, mk-2206, pifusertib, miransertib, ly-2780301, triciribine, xl-418, sr-13668, tas0612Rule: FDA's Pediatric Oncology Drug Approvals table names the drug. Source: FDA Pediatric Oncology Drug Approvals (content current as of 2026-03-03), 2026-11-12
- Registered studies open to children: yes · 11 interventional studies of capivasertib, afuresertib, ipatasertib, uprosertib, mk-2206, pifusertib, miransertib, ly-2780301, triciribine, xl-418, sr-13668, tas0612 include patients under 18; 7 are recruiting, not yet recruiting or activeRule: The registry's age group includes Child (birth to 17 years), which also counts studies that set no minimum age. Source: ClinicalTrials.gov search, 2026-11-12
Rare pediatric disease voucher. FDA, content current as of 29 Apr 2026: “As of February 3, 2026, enactment of the Consolidated Appropriations Act, 2026, the rare pediatric disease PRV program will sunset after September 30, 2029. FDA may not award any PRVs under this program after September 30, 2029.” Voucher sale prices are not shown here; they appear only as company-reported news. FDA: Rare Pediatric Disease Designation and Priority Review Voucher Programs
All 15 drugs and clinical candidates as a table
Each drug, stage and indication links to its Open Targets record, where the trials and approvals behind it are listed. Salt forms (for example a mesylate) are listed as Open Targets records them, as separate entries.