Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLUM9L7)

• DOT Name: Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3)
• Synonyms: PI3-kinase type 3; PI3K type 3; PtdIns-3-kinase type 3; EC 2.7.1.137; Phosphatidylinositol 3-kinase p100 subunit; Phosphoinositide-3-kinase class 3; hVps34
• Gene Name: PIK3C3
• Related Disease:
  Central nervous system neoplasm
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Bipolar disorder
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Chronic kidney disease
  Colon cancer
  Colon carcinoma
  Glioblastoma multiforme
  Hepatitis C virus infection
  Hypertrophic cardiomyopathy
  Hypothyroidism
  Kidney failure
  Non-small-cell lung cancer
  Pulmonary arterial hypertension
  Urinary bladder cancer
  Urinary bladder neoplasm
  Melanoma
  Neurodevelopmental disorder
  Non-insulin dependent diabetes
  Schizophrenia
  Acute respiratory failure
  Colorectal carcinoma
  Lung neoplasm
  Neoplasm
  Rheumatic fever
  Tuberous sclerosis
• UniProt ID: PK3C3_HUMAN
• PDB ID: 3IHY; 3LS8; 4OYS; 4PH4; 4UWF; 4UWG; 4UWH; 4UWK; 4UWL; 5ANL; 5ENN; 6HOG; 6HOH; 6I3U; 6YKG; 7BL1; 7RSJ; 7RSP; 7RSV; 8SOR; 8SRQ
• EC Number: 2.7.1.137
• Pfam ID: PF00454 ; PF00792 ; PF00613
• Sequence:
  MGEAEKFHYIYSCDLDINVQLKIGSLEGKREQKSYKAVLEDPMLKFSGLYQETCSDLYVT
  CQVFAEGKPLALPVRTSYKAFSTRWNWNEWLKLPVKYPDLPRNAQVALTIWDVYGPGKAV
  PVGGTTVSLFGKYGMFRQGMHDLKVWPNVEADGSEPTKTPGRTSSTLSEDQMSRLAKLTK
  AHRQGHMVKVDWLDRLTFREIEMINESEKRSSNFMYLMVEFRCVKCDDKEYGIVYYEKDG
  DESSPILTSFELVKVPDPQMSMENLVESKHHKLARSLRSGPSDHDLKPNAATRDQLNIIV
  SYPPTKQLTYEEQDLVWKFRYYLTNQEKALTKFLKCVNWDLPQEAKQALELLGKWKPMDV
  EDSLELLSSHYTNPTVRRYAVARLRQADDEDLLMYLLQLVQALKYENFDDIKNGLEPTKK
  DSQSSVSENVSNSGINSAEIDSSQIITSPLPSVSSPPPASKTKEVPDGENLEQDLCTFLI
  SRACKNSTLANYLYWYVIVECEDQDTQQRDPKTHEMYLNVMRRFSQALLKGDKSVRVMRS
  LLAAQQTFVDRLVHLMKAVQRESGNRKKKNERLQALLGDNEKMNLSDVELIPLPLEPQVK
  IRGIIPETATLFKSALMPAQLFFKTEDGGKYPVIFKHGDDLRQDQLILQIISLMDKLLRK
  ENLDLKLTPYKVLATSTKHGFMQFIQSVPVAEVLDTEGSIQNFFRKYAPSENGPNGISAE
  VMDTYVKSCAGYCVITYILGVGDRHLDNLLLTKTGKLFHIDFGYILGRDPKPLPPPMKLN
  KEMVEGMGGTQSEQYQEFRKQCYTAFLHLRRYSNLILNLFSLMVDANIPDIALEPDKTVK
  KVQDKFRLDLSDEEAVHYMQSLIDESVHALFAAVVEQIHKFAQYWRK
• Function: Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. As part of PI3KC3-C1, promotes endoplasmic reticulum membrane curvature formation prior to vesicle budding. Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for transport from early to late endosomes; (Microbial infection) Kinase activity is required for SARS coronavirus-2/SARS-CoV-2 replication.
• Tissue Specificity: Ubiquitously expressed, with a highest expression in skeletal muscle.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
  Phagosome (hsa04145)
  Apelin sig.ling pathway (hsa04371)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Tuberculosis (hsa05152)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
  Synthesis of PIPs at the early endosome membrane (R-HSA-1660516)
  Synthesis of PIPs at the late endosome membrane (R-HSA-1660517)
  Toll Like Receptor 9 (TLR9) Cascade (R-HSA-168138)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9679504)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9694676)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Antigen Presentation (R-HSA-983170)
  PI3K Cascade (R-HSA-109704)
• BioCyc Pathway: MetaCyc:HS01275-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Central nervous system neoplasm	DISFC18W	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[8]
Carcinoma	DISH9F1N	Strong	Biomarker	[9]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[10]
Colon cancer	DISVC52G	Strong	Biomarker	[11]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[12]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[13]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[14]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[15]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[16]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[17]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Melanoma	DIS1RRCY	moderate	Biomarker	[18]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[19]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[20]
Schizophrenia	DISSRV2N	Disputed	Genetic Variation	[21]
Acute respiratory failure	DIS5KQ5Y	Limited	Altered Expression	[22]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[23]
Lung neoplasm	DISVARNB	Limited	Altered Expression	[22]
Neoplasm	DISZKGEW	Limited	Altered Expression	[24]
Rheumatic fever	DISLUF66	Limited	Altered Expression	[22]
Tuberous sclerosis	DISEMUGZ	Limited	Altered Expression	[24]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) affects the response to substance of Temozolomide.	[41]
DTI-015	DMXZRW0	Approved	Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) affects the response to substance of DTI-015.	[41]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[34]
schisandrin A	DMWQ480	Investigative	schisandrin A decreases the phosphorylation of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[40]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[26]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[27]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[28]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[29]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[30]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[31]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[32]
Ceritinib	DMB920Z	Approved	Ceritinib decreases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[33]
AMEP	DMFELMQ	Phase 1	AMEP increases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[36]
EMODIN	DMAEDQG	Terminated	EMODIN increases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[38]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[39]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3).	[35]

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