Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZY806Z)

• DOT Name: PH-interacting protein (PHIP)
• Synonyms: PHIP; DDB1- and CUL4-associated factor 14; IRS-1 PH domain-binding protein; WD repeat-containing protein 11
• Gene Name: PHIP
• Related Disease:
  Neoplasm
  Obsolete developmental delay, intellectual disability, obesity, and dysmorphic features
  PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome
  Advanced cancer
  Intellectual disability
  Metastatic melanoma
  Sjogren syndrome
  Cornelia de Lange syndrome
  Lung cancer
  Lung carcinoma
  Melanoma
• UniProt ID: PHIP_HUMAN
• PDB ID: 3MB3 ; 5ENB ; 5ENC ; 5ENE ; 5ENF ; 5ENH ; 5ENI ; 5ENJ ; 5RJI ; 5RJJ ; 5RJK ; 5RJL ; 5RJM ; 5RJN ; 5RJO ; 5RJP ; 5RJQ ; 5RJR ; 5RJS ; 5RJT ; 5RJU ; 5RJV ; 5RJW ; 5RJX ; 5RJY ; 5RJZ ; 5RK0 ; 5RK1 ; 5RK2 ; 5RK3 ; 5RK4 ; 5RK5 ; 5RK6 ; 5RK7 ; 5RK8 ; 5RK9 ; 5RKA ; 5RKB ; 5RKC ; 5RKD ; 5RKE ; 5RKF ; 5RKG ; 5RKH ; 5RKI ; 5RKJ ; 5RKK ; 5RKL ; 5RKM ; 5RKN ; 5RKO ; 5RKP ; 5RKQ ; 5RKR ; 5RKS ; 5RKT ; 5RKU ; 5RKV ; 5RKW ; 5RKX ; 5RKY ; 5S8C ; 5S8D ; 5S8E ; 5S8F ; 5S8G ; 5S8H ; 5S8I ; 5S8J ; 5S8K ; 5S8L ; 5S8M ; 5S8N ; 5S8O ; 5S8P ; 5S8Q ; 5S8R ; 5S8S ; 5S8T ; 5S8U ; 5S8V ; 5S8W ; 5S8X ; 5S8Y ; 5S8Z ; 5S90 ; 5S91 ; 5S92 ; 5S93 ; 5S94 ; 5S95 ; 5S96 ; 5S97 ; 5S98 ; 5S99 ; 5S9A ; 5S9B ; 5S9C ; 5S9D ; 5S9E ; 5S9G ; 5S9J ; 7AV8 ; 7AV9 ; 7BBO ; 7BBP ; 7FUS ; 7FUT ; 7FUU ; 7FUV ; 7FUW ; 7FUX ; 7FUY ; 7FUZ ; 7FV0 ; 7FV1 ; 7FV2 ; 7FV3 ; 7FV4 ; 7FV5 ; 7FV6 ; 7FV7 ; 7FV8 ; 7FV9 ; 7FVA ; 7FVB ; 7FVC ; 7FVD ; 7FVE ; 7FVF ; 7FVG ; 7FVH ; 7FVI ; 7FVJ ; 7FVK ; 7FVL ; 7FVM ; 7FVN ; 7FVO ; 7FVP ; 7FVQ ; 7FVR ; 8BW2 ; 8BW3 ; 8BW4
• Pfam ID: PF00439 ; PF00400
• Sequence:
  MSCERKGLSELRSELYFLIARFLEDGPCQQAAQVLIREVAEKELLPRRTDWTGKEHPRTY
  QNLVKYYRHLAPDHLLQICHRLGPLLEQEIPQSVPGVQTLLGAGRQSLLRTNKSCKHVVW
  KGSALAALHCGRPPESPVNYGSPPSIADTLFSRKLNGKYRLERLVPTAVYQHMKMHKRIL
  GHLSSVYCVTFDRTGRRIFTGSDDCLVKIWATDDGRLLATLRGHAAEISDMAVNYENTMI
  AAGSCDKMIRVWCLRTCAPLAVLQGHSASITSLQFSPLCSGSKRYLSSTGADGTICFWLW
  DAGTLKINPRPAKFTERPRPGVQMICSSFSAGGMFLATGSTDHIIRVYFFGSGQPEKISE
  LEFHTDKVDSIQFSNTSNRFVSGSRDGTARIWQFKRREWKSILLDMATRPAGQNLQGIED
  KITKMKVTMVAWDRHDNTVITAVNNMTLKVWNSYTGQLIHVLMGHEDEVFVLEPHPFDPR
  VLFSAGHDGNVIVWDLARGVKIRSYFNMIEGQGHGAVFDCKCSPDGQHFACTDSHGHLLI
  FGFGSSSKYDKIADQMFFHSDYRPLIRDANNFVLDEQTQQAPHLMPPPFLVDVDGNPHPS
  RYQRLVPGRENCREEQLIPQMGVTSSGLNQVLSQQANQEISPLDSMIQRLQQEQDLRRSG
  EAVISNTSRLSRGSISSTSEVHSPPNVGLRRSGQIEGVRQMHSNAPRSEIATERDLVAWS
  RRVVVPELSAGVASRQEEWRTAKGEEEIKTYRSEEKRKHLTVPKENKIPTVSKNHAHEHF
  LDLGESKKQQTNQHNYRTRSALEETPRPSEEIENGSSSSDEGEVVAVSGGTSEEEERAWH
  SDGSSSDYSSDYSDWTADAGINLQPPKKVPKNKTKKAESSSDEEEESEKQKQKQIKKEKK
  KVNEEKDGPISPKKKKPKERKQKRLAVGELTENGLTLEEWLPSTWITDTIPRRCPFVPQM
  GDEVYYFRQGHEAYVEMARKNKIYSINPKKQPWHKMELREQELMKIVGIKYEVGLPTLCC
  LKLAFLDPDTGKLTGGSFTMKYHDMPDVIDFLVLRQQFDDAKYRRWNIGDRFRSVIDDAW
  WFGTIESQEPLQLEYPDSLFQCYNVCWDNGDTEKMSPWDMELIPNNAVFPEELGTSVPLT
  DGECRSLIYKPLDGEWGTNPRDEECERIVAGINQLMTLDIASAFVAPVDLQAYPMYCTVV
  AYPTDLSTIKQRLENRFYRRVSSLMWEVRYIEHNTRTFNEPGSPIVKSAKFVTDLLLHFI
  KDQTCYNIIPLYNSMKKKVLSDSEDEEKDADVPGTSTRKRKDHQPRRRLRNRAQSYDIQA
  WKKQCEELLNLIFQCEDSEPFRQPVDLLEYPDYRDIIDTPMDFATVRETLEAGNYESPME
  LCKDVRLIFSNSKAYTPSKRSRIYSMSLRLSAFFEEHISSVLSDYKSALRFHKRNTITKR
  RKKRNRSSSVSSSAASSPERKKRILKPQLKSESSTSAFSTPTRSIPPRHNAAQINGKTES
  SSVVRTRSNRVVVDPVVTEQPSTSSAAKTFITKANASAIPGKTILENSVKHSKALNTLSS
  PGQSSFSHGTRNNSAKENMEKEKPVKRKMKSSVLPKASTLSKSSAVIEQGDCKNNALVPG
  TIQVNGHGGQPSKLVKRGPGRKPKVEVNTNSGEIIHKKRGRKPKKLQYAKPEDLEQNNVH
  PIRDEVLPSSTCNFLSETNNVKEDLLQKKNRGGRKPKRKMKTQKLDADLLVPASVKVLRR
  SNRKKIDDPIDEEEEFEELKGSEPHMRTRNQGRRTAFYNEDDSEEEQRQLLFEDTSLTFG
  TSSRGRVRKLTEKAKANLIGW
• Function: Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization.
• Tissue Specificity: Expressed in myeloma and epidermoid carcinoma cell lines.
• Reactome Pathway: RHOBTB2 GTPase cycle (R-HSA-9013418)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Obsolete developmental delay, intellectual disability, obesity, and dysmorphic features	DISJENI6	Definitive	Autosomal dominant	[2]
PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome	DISE8BAQ	Definitive	Autosomal dominant	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Metastatic melanoma	DISSL43L	Strong	Biomarker	[4]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[6]
Cornelia de Lange syndrome	DISEQSXO	moderate	Biomarker	[7]
Lung cancer	DISCM4YA	Limited	Biomarker	[1]
Lung carcinoma	DISTR26C	Limited	Biomarker	[1]
Melanoma	DIS1RRCY	Limited	Biomarker	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	PH-interacting protein (PHIP) affects the response to substance of Cisplatin.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of PH-interacting protein (PHIP).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of PH-interacting protein (PHIP).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PH-interacting protein (PHIP).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of PH-interacting protein (PHIP).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of PH-interacting protein (PHIP).	[12]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of PH-interacting protein (PHIP).	[13]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of PH-interacting protein (PHIP).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of PH-interacting protein (PHIP).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of PH-interacting protein (PHIP).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of PH-interacting protein (PHIP).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of PH-interacting protein (PHIP).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of PH-interacting protein (PHIP).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of PH-interacting protein (PHIP).	[16]

References

• [1] PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer.Proc Natl Acad Sci U S A. 2018 Jun 19;115(25):E5766-E5775. doi: 10.1073/pnas.1804779115. Epub 2018 Jun 4.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Role of Elevated PHIP Copy Number as a Prognostic and Progression Marker for Cutaneous Melanoma.Clin Cancer Res. 2018 Sep 1;24(17):4119-4125. doi: 10.1158/1078-0432.CCR-18-0791. Epub 2018 May 18.
• [5] A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency. Eur J Hum Genet. 2018 Jan;26(1):54-63. doi: 10.1038/s41431-017-0039-5. Epub 2017 Dec 5.
• [6] Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjgren's syndrome.Nat Genet. 2013 Nov;45(11):1284-92. doi: 10.1038/ng.2792. Epub 2013 Oct 6.
• [7] Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome.J Hum Genet. 2019 Oct;64(10):967-978. doi: 10.1038/s10038-019-0643-z. Epub 2019 Jul 23.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [14] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.