Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTGBPJE)

• DTT Name: PI3-kinase delta (PIK3CD)
• Synonyms: PtdIns-3-kinase subunit p110-delta; PtdIns-3-kinase subunit delta; Phosphoinositide 3-kinase delta; Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, delta isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit delta; PI3Kdelta; PI3K-delta; PI3-kinase subunit delta; PI3-kinase p110 subunit delta; P110delta
• Gene Name: PIK3CD
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: PK3CD_HUMAN
• TTD ID: T67849
• EC Number: EC 2.7.1.153
• Sequence:
  MPPGVDCPMEFWTKEENQSVVVDFLLPTGVYLNFPVSRNANLSTIKQLLWHRAQYEPLFH
  MLSGPEAYVFTCINQTAEQQELEDEQRRLCDVQPFLPVLRLVAREGDRVKKLINSQISLL
  IGKGLHEFDSLCDPEVNDFRAKMCQFCEEAAARRQQLGWEAWLQYSFPLQLEPSAQTWGP
  GTLRLPNRALLVNVKFEGSEESFTFQVSTKDVPLALMACALRKKATVFRQPLVEQPEDYT
  LQVNGRHEYLYGSYPLCQFQYICSCLHSGLTPHLTMVHSSSILAMRDEQSNPAPQVQKPR
  AKPPPIPAKKPSSVSLWSLEQPFRIELIQGSKVNADERMKLVVQAGLFHGNEMLCKTVSS
  SEVSVCSEPVWKQRLEFDINICDLPRMARLCFALYAVIEKAKKARSTKKKSKKADCPIAW
  ANLMLFDYKDQLKTGERCLYMWPSVPDEKGELLNPTGTVRSNPNTDSAAALLICLPEVAP
  HPVYYPALEKILELGRHSECVHVTEEEQLQLREILERRGSGELYEHEKDLVWKLRHEVQE
  HFPEALARLLLVTKWNKHEDVAQMLYLLCSWPELPVLSALELLDFSFPDCHVGSFAIKSL
  RKLTDDELFQYLLQLVQVLKYESYLDCELTKFLLDRALANRKIGHFLFWHLRSEMHVPSV
  ALRFGLILEAYCRGSTHHMKVLMKQGEALSKLKALNDFVKLSSQKTPKPQTKELMHLCMR
  QEAYLEALSHLQSPLDPSTLLAEVCVEQCTFMDSKMKPLWIMYSNEEAGSGGSVGIIFKN
  GDDLRQDMLTLQMIQLMDVLWKQEGLDLRMTPYGCLPTGDRTGLIEVVLRSDTIANIQLN
  KSNMAATAAFNKDALLNWLKSKNPGEALDRAIEEFTLSCAGYCVATYVLGIGDRHSDNIM
  IRESGQLFHIDFGHFLGNFKTKFGINRERVPFILTYDFVHVIQQGKTNNSEKFERFRGYC
  ERAYTILRRHGLLFLHLFALMRAAGLPELSCSKDIQYLKDSLALGKTEEEALKHFRVKFN
  EALRESWKTKVNWLAHNVSKDNRQ
• Function: Phosphoinositide-3-kinase (PI3K) that phosphorylates 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. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  HIF-1 signaling pathway (hsa04066)
  FoxO signaling pathway (hsa04068)
  Phosphatidylinositol signaling system (hsa04070)
  Sphingolipid signaling pathway (hsa04071)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Apoptosis (hsa04210)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  VEGF signaling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Platelet activation (hsa04611)
  Toll-like receptor signaling pathway (hsa04620)
  Jak-STAT signaling pathway (hsa04630)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  Fc epsilon RI signaling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  TNF signaling pathway (hsa04668)
  Leukocyte transendothelial migration (hsa04670)
  Neurotrophin signaling pathway (hsa04722)
  Cholinergic synapse (hsa04725)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin signaling pathway (hsa04910)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen signaling pathway (hsa04915)
  Prolactin signaling pathway (hsa04917)
  Thyroid hormone signaling pathway (hsa04919)
  Oxytocin signaling pathway (hsa04921)
  Regulation of lipolysis in adipocytes (hsa04923)
  Type II diabetes mellitus (hsa04930)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Carbohydrate digestion and absorption (hsa04973)
  Bacterial invasion of epithelial cells (hsa05100)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  Colorectal cancer (hsa05210)
  Renal cell carcinoma (hsa05211)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  G beta (R-HSA-392451)
  Interleukin-3, 5 and GM-CSF signaling (R-HSA-512988)
  Interleukin receptor SHC signaling (R-HSA-912526)
  Regulation of signaling by CBL (R-HSA-912631)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  GPVI-mediated activation cascade (R-HSA-114604)
• BioCyc Pathway: MetaCyc:ENSG00000171608-MON

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BAY 80-6946	DMLOS5R	Follicular lymphoma	2A80	Approved	[2]
Idelalisib	DM602WT	Chronic lymphocytic leukaemia	2A82.0	Approved	[1]
IPI-145	DMWA24P	Follicular lymphoma	2A80	Approved	[3]
Leniolisib	DMWAD93	Stomach cancer	2B72	Approved	[4]
Umbralisib	DMYRBO1	Follicular lymphoma	2A80	Approved	[5]

15 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Buparlisib	DM1WEHC	Breast cancer	2C60-2C65	Phase 3	[6]
AZD8154	DMK13L1	Asthma	CA23	Phase 2	[7]
INCB50465	DMZJP2T	Diffuse large B-cell lymphoma	2A81	Phase 2	[8]
ME-401	DMK0UOY	Follicular lymphoma	2A80	Phase 2	[8]
Parsaclisib	DMYBIFS	Follicular lymphoma	2A80	Phase 2	[9]
RP6530	DMYILGK	Chronic lymphocytic leukaemia	2A82.0	Phase 2	[8]
INCB40093	DMED9QV	Lymphoma	2A80-2A86	Phase 1/2	[10]
PA-799	DMLSYJQ	Colorectal cancer	2B91.Z	Phase 1/2	[11]
ZX-101A	DM65AV2	Chronic lymphocytic leukaemia	2A82.0	Phase 1/2	[12]
AMG 319	DM9P0NA	Hematologic tumour	2B33.Y	Phase 1	[13]
BGB-10188	DM84LXE	B-cell lymphoma	2A86	Phase 1	[14]
GS-9820	DMNX3US	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[15]
GS-9901	DMGHN98	Haematological malignancy	2B33.Y	Phase 1	[16]
GSK2292767	DMIX891	Asthma	CA23	Phase 1	[17]
HMPL-689	DMEGN5I	Lymphoma	2A80-2A86	Phase 1	[18]

1 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pyrrolo[2,3-d]pyrimidine derivative 28	DMXRJI2	N. A.	N. A.	Patented	[19]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
XL-499	DMINSA5	Solid tumour/cancer	2A00-2F9Z	Preclinical	[20]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Wortmannin	DM8EVK5	Haematological malignancy	2B33.Y	Terminated	[21]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxylate	DM3FH02	Discovery agent	N.A.	Investigative	[22]
ETP-46321	DMO2PY8	Rheumatoid arthritis	FA20	Investigative	[23]
IC87114	DMM50ED	Discovery agent	N.A.	Investigative	[21]
IC980033	DM8L6WB	Discovery agent	N.A.	Investigative	[21]
LY-292223	DML36ZE	Discovery agent	N.A.	Investigative	[22]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2C82	Bone marrow	4.31E-16	-0.37	-0.91
Rheumatoid arthritis	FA20	Synovial tissue	3.63E-02	-0.39	-1.39
Breast cancer	2C82	Breast tissue	1.03E-01	-0.08	-0.28

References

• [1] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [2] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [3] PI3K-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.
• [4] Effective "activated PI3K syndrome"-targeted therapy with the PI3K inhibitor leniolisib. Blood. 2017 Nov 23;130(21):2307-2316.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [6] Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
• [7] Discovery of AZD8154, a Dual PI3Kgamma-delta Inhibitor for the Treatment of Asthma. J Med Chem. 2021 Jun 24;64(12):8053-8075.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Parsaclisib, a potent and highly selective PI3K inhibitor, in patients with relapsed or refractory B-cell malignancies. Blood. 2019 Apr 18;133(16):1742-1752.
• [10] INCB40093 is a selective PI3Kdelta inhibitor with potent antiproliferative activity against human B-cell tumors.
• [11] The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
• [12] Clinical pipeline report, company report or official report of Zenshine Pharmaceuticals
• [13] National Cancer Institute Drug Dictionary (drug id 696292).
• [14] ClinicalTrials.gov (NCT04282018) Brief Title: Study of BGB-10188 as Monotherapy, and in Combination With Zanubrutinib, and Tislelizumab. U.S. National Institutes of Health.
• [15] National Cancer Institute Drug Dictionary (drug id 741949).
• [16] Clinical pipeline report, company report or official report of Gilead.
• [17] Translation of Inhaled Drug Optimization Strategies into Clinical Pharmacokinetics and Pharmacodynamics Using GSK2292767A, a Novel Inhaled Phosphoinositide 3-Kinase delta Inhibitor. J Pharmacol Exp Ther. 2019 Jun;369(3):443-453.
• [18] Clinical pipeline report, company report or official report of Hutchison MediPharma.
• [19] Pyrrolo[2,3-d]pyrimidines active as Btk inhibitors.Expert Opin Ther Pat. 2017 Dec;27(12):1305-1318.
• [20] Clinical pipeline report, company report or official report of Exelixis.
• [21] Selective role of PI3K delta in neutrophil inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308(4):764-9.
• [22] LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family. Bioorg Med Chem Lett. 2001 Apr 9;11(7):909-13.
• [23] ETP-46321, a dual p110alpha/ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis. Biochem Pharmacol. 2016 Apr 15;106:56-69.