Target Information

Target General Infomation
Target ID
T95913
Former ID
TTDR00356
Target Name
Phosphoinositide 3 kinase
Gene Name
PIK3CG
Synonyms
PI 3-kinase; PI3K; Phosphoinositol-3 kinase; PI3-kinase p110 subunit gamma; PI3K; PI3Kgamma; Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, gamma isoform; Phosphoinositide 3-Kinase gamma; PtdIns-3-kinase p110; PIK3CG
Target Type
Successful
Disease Advanced solid tumor [ICD9: 140-199; ICD10: C00-C75, C7A, C7B]
Arthritis [ICD9: 710-719; ICD10: M00-M25]
Advanced solid tumor; Non-hodgkin's lymphoma [ICD9: 140-199, 200, 202, 202.8, 210-229; ICD10: C00-C75, C7A, C7B, C81-C86, C82-C85, D10-D36, D3A]
Angioedema; Myocardial infarction [ICD9: 277.6, 410, 995.1; ICD10: D84.1, I21, I22, T78.3]
Breast cancer [ICD9: 174, 175; ICD10: C50]
Bacterial infections [ICD9: 001-009, 010-018, 020-027, 030-041, 080-088, 090-099, 100-104; ICD10: A00-B99]
Cardiovascular disorder [ICD10: I00-I99]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Diffuse large B-cell lymphoma [ICD9: 200; ICD10: C83.3]
Enthesopathy; Type 2 diabetes [ICD9:726, 250; ICD10: M76-M77.9, E11]
Endometrial cancer [ICD9: 182; ICD10: C54.1]
Glioma [ICD9: 191; ICD10: C71]
Hematologic malignancies [ICD9: 200-209; ICD10: C81-C86]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86]
Metastatic breast cancer; Endometrial cancer; Lymphoma [ICD9: 140-199, 140-229, 174, 175, 182.0, 202.8, 210-229; ICD10: C50, C81-C86]
Non-hodgkin's lymphoma [ICD10: C85]
Prostate cancer [ICD9: 185; ICD10: C61]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Type 2 diabetes [ICD9: 250; ICD10: E11]
Function
Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4- phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5- bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). 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 in breast cancer cells 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. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.
BioChemical Class
Kinase
Target Validation
T17917
UniProt ID
P48736
EC Number
EC 2.7.11.1
Sequence
MELENYKQPVVLREDNCRRRRRMKPRSAAASLSSMELIPIEFVLPTSQRKCKSPETALLH
VAGHGNVEQMKAQVWLRALETSVAADFYHRLGPHHFLLLYQKKGQWYEIYDKYQVVQTLD
CLRYWKATHRSPGQIHLVQRHPPSEESQAFQRQLTALIGYDVTDVSNVHDDELEFTRRGL
VTPRMAEVASRDPKLYAMHPWVTSKPLPEYLWKKIANNCIFIVIHRSTTSQTIKVSPDDT
PGAILQSFFTKMAKKKSLMDIPESQSEQDFVLRVCGRDEYLVGETPIKNFQWVRHCLKNG
EEIHVVLDTPPDPALDEVRKEEWPLVDDCTGVTGYHEQLTIHGKDHESVFTVSLWDCDRK
FRVKIRGIDIPVLPRNTDLTVFVEANIQHGQQVLCQRRTSPKPFTEEVLWNVWLEFSIKI
KDLPKGALLNLQIYCGKAPALSSKASAESPSSESKGKVQLLYYVNLLLIDHRFLLRRGEY
VLHMWQISGKGEDQGSFNADKLTSATNPDKENSMSISILLDNYCHPIALPKHQPTPDPEG
DRVRAEMPNQLRKQLEAIIATDPLNPLTAEDKELLWHFRYESLKHPKAYPKLFSSVKWGQ
QEIVAKTYQLLARREVWDQSALDVGLTMQLLDCNFSDENVRAIAVQKLESLEDDDVLHYL
LQLVQAVKFEPYHDSALARFLLKRGLRNKRIGHFLFWFLRSEIAQSRHYQQRFAVILEAY
LRGCGTAMLHDFTQQVQVIEMLQKVTLDIKSLSAEKYDVSSQVISQLKQKLENLQNSQLP
ESFRVPYDPGLKAGALAIEKCKVMASKKKPLWLEFKCADPTALSNETIGIIFKHGDDLRQ
DMLILQILRIMESIWETESLDLCLLPYGCISTGDKIGMIEIVKDATTIAKIQQSTVGNTG
AFKDEVLNHWLKEKSPTEEKFQAAVERFVYSCAGYCVATFVLGIGDRHNDNIMITETGNL
FHIDFGHILGNYKSFLGINKERVPFVLTPDFLFVMGTSGKKTSPHFQKFQDICVKAYLAL
RHHTNLLIILFSMMLMTGMPQLTSKEDIEYIRDALTVGKNEEDAKKYFLDQIEVCRDKGW
TVQFNWFLHLVLGIKQGEKHSA
Structure
1E8Y; 1E8Z; 1HE8; 2A4Z; 2A5U; 2CHW; 2CHX; 2CHZ; 2V4L; 3APC; 3APD; 3APF; 3CSF; 3CST; 3DBS; 3DPD; 3ENE; 3IBE; 3L08; 3L13; 3L16; 3L17; 3L54; 3LJ3; 3MJW; 3ML8; 3ML9; 3NZS; 3NZU; 3OAW; 3P2B; 3PRE; 3PRZ; 3PS6; 3QAQ; 3QAR; 3QJZ; 3QK0; 3R7Q; 3R7R; 3S2A; 3SD5; 3T8M; 3TJP; 3TL5; 3ZVV; 3ZW3; 4ANU; 4ANV; 4ANW; 4ANX; 4AOF; 4DK5; 4EZJ; 4EZK; 4EZL; 4F1S; 4FA6; 4FAD; 4FHJ; 4FHK; 4FJY; 4FJZ; 4FLH; 4FUL; 4G11; 4GB9; 4HLE; 4HVB; 4J6I; 4KZ0; 4KZC; 4PS3; 4PS7; 4PS8; 4URK; 4WWN; 4WWO; 4WWP; 2ENQ; 2RD0; 3HHM; 3HIZ; 3ZIM; 4JPS; 4L1B; 4L23; 4L2Y; 4OVU; 4OVV; 4TUU; 4TV3; 4WAF
Drugs and Mode of Action
Drug(s) CHU Drug Info Registered Enthesopathy; Type 2 diabetes [1]
BAY 80-6946 Drug Info Phase 3 Non-hodgkin's lymphoma [2], [3]
Buparlisib Drug Info Phase 3 Breast cancer [4], [5]
IPI-145 Drug Info Phase 3 Arthritis [6], [7]
Rigosertib Drug Info Phase 3 Solid tumours [8], [9]
BEZ235 Drug Info Phase 2 Solid tumours [10], [11]
CLR-1404 Drug Info Phase 2 Cancer [12]
GDC0941 Drug Info Phase 2 Advanced solid tumor; Non-hodgkin's lymphoma [13], [14]
PF-04691502 Drug Info Phase 2 Endometrial cancer [15], [16]
PF-05212384 Drug Info Phase 2 Cancer [17], [18]
PX-866 Drug Info Phase 2 Cancer [19], [20]
SAR245409 Drug Info Phase 2 Cancer [21]
XL147 Drug Info Phase 2 Cancer [22], [23]
BGT226 Drug Info Phase 1/2 Solid tumours [24], [25]
CLR-1401 Drug Info Phase 1/2 Cancer [26]
CLR457 Drug Info Phase 1/2 Advanced solid tumor [27]
TG100-115 Drug Info Phase 1/2 Angioedema; Myocardial infarction [28], [29]
CH-5132799 Drug Info Phase 1 Solid tumours [30], [31]
CUDC-907 Drug Info Phase 1 Diffuse large B-cell lymphoma [32]
DS-7423 Drug Info Phase 1 Solid tumours [33]
GDC-0980 Drug Info Phase 1 Advanced solid tumor; Non-hodgkin's lymphoma [34]
GSK2126458 Drug Info Phase 1 Lymphoma [35]
P-7170 Drug Info Phase 1 Cancer [36]
PA-799 Drug Info Phase 1 Solid tumours [37]
Perifosine Drug Info Phase 1 Solid tumours [38], [39]
PQR309 Drug Info Phase 1 Pain [40]
SAR245408 + MSC1936369B Drug Info Phase 1 Solid tumours [41]
SAR245409/MSC1936369B combination therapy Drug Info Phase 1 Solid tumours [41]
SF1126 Drug Info Phase 1 Solid tumours [42]
VS-5584 Drug Info Phase 1 Solid tumours [43], [44]
ZSTK474 Drug Info Phase 1 Cancer [45], [46]
Adyvia Drug Info Discontinued in Phase 2 Type 2 diabetes [47]
GDC-0084 Drug Info Discontinued in Phase 1 Glioma [48]
GSK1059615 Drug Info Discontinued in Phase 1 Metastatic breast cancer; Endometrial cancer; Lymphoma [49]
LY294002 Drug Info Terminated Cancer [50], [51]
PX-867 Drug Info Terminated Cardiovascular disorder [52]
SCR-44001 Drug Info Terminated Cancer [53]
Wortmannin Drug Info Terminated Hematologic malignancies [54], [55]
Inhibitor 2-(4-Morpholinyl)-8-Phenyl-4h-1-Benzopyran-4-One Drug Info [56]
3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol Drug Info [57]
5-QUINOXALIN-6-YLMETHYLENE-THIAZOLIDINE-2,4-DIONE Drug Info [58]
AEZS-126 Drug Info [59]
AS-604850 Drug Info [60]
BAG956 Drug Info [61]
Buparlisib Drug Info [62]
CH-5132799 Drug Info [30]
CHU Drug Info [63]
CLR-1401 Drug Info [59]
CLR-1404 Drug Info [59]
CU-906 Drug Info [59]
CZC 24832 Drug Info [64]
CZC-19091 Drug Info [63]
Dual PI3K/mTOR inhibitors Drug Info [59]
GDC-0084 Drug Info [65]
GDC0941 Drug Info [61], [62]
GSK1059615 Drug Info [62]
Her2- and PSA-targeted TGX-D1 Drug Info [66]
HM-5016699 Drug Info [59]
HS-173 Drug Info [67]
KU-0060648 Drug Info [68]
LOR-220 Drug Info [59]
LY-292223 Drug Info [69]
LY-293646 Drug Info [69]
LY294002 Drug Info [70]
Multiform PI3K inhibitors Drug Info [59]
Myricetin Drug Info [56]
P-6915 Drug Info [59]
P-7170 Drug Info [59]
PF-03772304 Drug Info [71]
PF-4989216 Drug Info [59]
PI-103 Drug Info [61]
PI-3065 Drug Info [72]
PIK-75 Drug Info [57]
PKI-402 Drug Info [73]
PP121 Drug Info [74]
PQR309 Drug Info [59]
PX-866 Drug Info [62]
SAR245408 + MSC1936369B Drug Info [63]
SAR245409 Drug Info [75]
SAR245409/MSC1936369B combination therapy Drug Info [63]
SCR-44001 Drug Info [76]
TG100-115 Drug Info [77], [78], [79]
TGX-221 Drug Info [80]
VE-822 Drug Info [81]
Wortmannin Drug Info [82], [83], [61]
WX-037 Drug Info [59]
Modulator Adyvia Drug Info
BAY 80-6946 Drug Info
BEZ235 Drug Info
BGT226 Drug Info [24]
CLR457 Drug Info [84]
CUDC-907 Drug Info
DS-7423 Drug Info [85]
GDC-0980 Drug Info [86]
GSK2126458 Drug Info
IPI-145 Drug Info [6]
PA-799 Drug Info
Perifosine Drug Info
PF-04691502 Drug Info
PF-05212384 Drug Info [17]
PX-867 Drug Info [87]
Rigosertib Drug Info [8]
SF1126 Drug Info
VS-5584 Drug Info [43]
XL147 Drug Info
ZSTK474 Drug Info [45]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Inositol phosphate metabolism
ErbB signaling pathway
Ras signaling pathway
Rap1 signaling pathway
cGMP-PKG signaling pathway
cAMP signaling pathway
Chemokine signaling pathway
HIF-1 signaling pathway
FoxO signaling pathway
Phosphatidylinositol signaling system
Sphingolipid signaling pathway
mTOR signaling pathway
PI3K-Akt signaling pathway
AMPK signaling pathway
Apoptosis
Adrenergic signaling in cardiomyocytes
VEGF signaling pathway
Osteoclast differentiation
Focal adhesion
Signaling pathways regulating pluripotency of stem cells
Platelet activation
Toll-like receptor signaling pathway
Jak-STAT signaling pathway
Natural killer cell mediated cytotoxicity
T cell receptor signaling pathway
B cell receptor signaling pathway
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
TNF signaling pathway
Leukocyte transendothelial migration
Neurotrophin signaling pathway
Cholinergic synapse
Inflammatory mediator regulation of TRP channels
Regulation of actin cytoskeleton
Insulin signaling pathway
Progesterone-mediated oocyte maturation
Estrogen signaling pathway
Prolactin signaling pathway
Thyroid hormone signaling pathway
Oxytocin signaling pathway
Regulation of lipolysis in adipocytes
Type II diabetes mellitus
Non-alcoholic fatty liver disease (NAFLD)
Aldosterone-regulated sodium reabsorption
Carbohydrate digestion and absorption
Bacterial invasion of epithelial cells
Chagas disease (American trypanosomiasis)
Toxoplasmosis
Amoebiasis
Hepatitis C
Hepatitis B
Measles
Influenza A
HTLV-I infection
Epstein-Barr virus infection
Pathways in cancer
Viral carcinogenesis
Proteoglycans in cancer
MicroRNAs in cancer
Colorectal cancer
Renal cell carcinoma
Pancreatic cancer
Endometrial cancer
Glioma
Prostate cancer
Melanoma
Chronic myeloid leukemia
Acute myeloid leukemia
Small cell lung cancer
Non-small cell lung cancer
Central carbon metabolism in cancer
Choline metabolism in cancer
PathWhiz Pathway Inositol Metabolism
Phosphatidylinositol Phosphate Metabolism
Intracellular Signalling Through Adenosine Receptor A2a and Adenosine
Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
Fc Epsilon Receptor I Signaling in Mast Cells
Reactome PI3K Cascade
GPVI-mediated activation cascade
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
PI3K events in ERBB4 signaling
PIP3 activates AKT signaling
GAB1 signalosome
PI3K events in ERBB2 signaling
PI3K/AKT activation
Role of phospholipids in phagocytosis
Tie2 Signaling
Constitutive Signaling by Aberrant PI3K in Cancer
DAP12 signaling
Role of LAT2/NTAL/LAB on calcium mobilization
Nephrin interactions
Costimulation by the CD28 family
CD28 dependent PI3K/Akt signaling
gamma signalling through PI3Kgamma
G alpha (q) signalling events
G alpha (12/13) signalling events
VEGFA-VEGFR2 Pathway
Interleukin-3, 5 and GM-CSF signaling
Constitutive Signaling by EGFRvIII
FGFR1
FGFR2
FGFR3
FGFR4
Interleukin receptor SHC signaling
Regulation of signaling by CBL
WikiPathways Toll-like receptor signaling pathway
Serotonin HTR1 Group and FOS Pathway
DNA Damage Response (only ATM dependent)
G13 Signaling Pathway
Regulation of Actin Cytoskeleton
Insulin Signaling
IL-4 Signaling Pathway
Copper homeostasis
Signaling of Hepatocyte Growth Factor Receptor
Transcriptional activation by NRF2
IL1 and megakaryotyces in obesity
Signaling by ERBB4
Signaling by ERBB2
Fc epsilon receptor (FCERI) signaling
PI Metabolism
Interleukin-2 signaling
Fcgamma receptor (FCGR) dependent phagocytosis
Signaling by SCF-KIT
DAP12 interactions
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
Gastrin-CREB signalling pathway via PKC and MAPK
PIP3 activates AKT signaling
Integrated Pancreatic Cancer Pathway
Prostate Cancer
Signaling Pathways in Glioblastoma
TSLP Signaling Pathway
Regulation of Microtubule Cytoskeleton
TSH signaling pathway
SREBP signalling
TCR signaling
Signaling by PDGF
Signaling by Insulin receptor
Signaling by FGFR
Signaling by EGFR
NGF signalling via TRKA from the plasma membrane
Nephrin interactions
Interleukin-3, 5 and GM-CSF signaling
GPVI-mediated activation cascade
GPCR downstream signaling
Costimulation by the CD28 family
Cell surface interactions at the vascular wall
MicroRNAs in cardiomyocyte hypertrophy
Angiogenesis
Regulation of toll-like receptor signaling pathway
AMPK Signaling
References
REF 1Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027532)
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7875).
REF 3Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031792)
REF 4ClinicalTrials.gov (NCT01610284) Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor. U.S. National Institutes of Health.
REF 5(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7878).
REF 6PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013 Nov 21;20(11):1364-74.
REF 7(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7795).
REF 8Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies. Clin Cancer Res. 2014 Mar 15;20(6):1656-65.
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REF 10(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7950).
REF 11Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026094)
REF 12ClinicalTrials.gov (NCT01778088) Open-Label Study of I-131-CLR1404 in Subjects With Recurrent Glioma. U.S. National Institutes of Health.
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REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027517)
REF 15ClinicalTrials.gov (NCT01430585) Pre-Operative Study of PF-4691502 With Letrozole Compared To Letrozole Alone In Patients With Early Breast Cancer. U.S. National Institutes of Health.
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REF 17First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin Cancer Res. 2015 Apr 15;21(8):1888-95.
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REF 19ClinicalTrials.gov (NCT01331083) A Phase II Study of PX-866 in Patients With Recurrent or Metastatic Castration Resistant Prostate Cancer. U.S. National Institutes of Health.
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REF 21ClinicalTrials.gov (NCT01936363) Trial of Pimasertib With SAR245409 or Placebo in Ovarian Cancer. U.S. National Institutes of Health.
REF 22Phase II study of the PI3K inhibitor pilaralisib (SAR245408; XL147) in patients with advanced or recurrent endometrial carcinoma. Gynecol Oncol. 2015 Feb;136(2):246-53.
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REF 24Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma. Anticancer Drugs. 2012 Jan;23(1):131-8.
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REF 26ClinicalTrials.gov (NCT01516905) PET/CT Imaging of Malignant Brain Tumors With a Novel Radioiodinated Phospholipid Ether Analogue 124I-NM404. U.S. National Institutes of Health.
REF 27ClinicalTrials.gov (NCT02189174) Study of CLR457 Administered Orally in Adult Patients With Advanced Solid Malignancies. U.S. National Institutes of Health.
REF 28Pharmacologic therapeutics for cardiac reperfusion injury. Expert Opin Emerg Drugs. 2007 Sep;12(3):367-88.
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REF 30The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
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REF 32Clinical pipeline report, company report or official report of Curis.
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REF 34Clinical pipeline report, company report or official report of Genentech (2011).
REF 35Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma. Mol Cancer Ther. 2015 Feb;14(2):429-39.
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REF 41ClinicalTrials.gov (NCT01357330) Oral SAR245408 (XL147) and Oral MSC1936369B in Patients With Locally Advanced or Metastatic Solid Tumors. U.S. National Institutes of Health.
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REF 45Combination of the PI3K inhibitor ZSTK474 with a PSMA-targeted immunotoxin accelerates apoptosis and regression of prostate cancer. Neoplasia. 2013 Oct;15(10):1172-83.
REF 46(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7965).
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