Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8SYN47)

• DOT Name: DENN domain-containing protein 4C (DENND4C)
• Gene Name: DENND4C
• UniProt ID: DEN4C_HUMAN
• Pfam ID: PF03455 ; PF02141 ; PF03456
• Sequence:
  MIEDKGPRVTDYFVVAGLTDTSTLLDQEINRLDTKSTGPKAPITDIAIIIKSAGETVPEG
  YTCVEATPSALQANLNYGSLKSPELFLCYKRGRDKPPLTDIGVLYEGKERLIPGCEVILA
  TPYGRCANVNNSSTTSQRIFITYRRAPPVRPQNSLAVTDICVIVTSKGETPPHTFCKVDK
  NLNCGMWGSSVFLCYKKSVPASNAIAYKAGLIFRYPEEDYESFPLSESDVPLFCLPMGAT
  IECWDPETKYPLPVFSTFVLTGSSAKKVYGAAIQFYEPYSRELLSEKQLMHLGLLTPVER
  KMVSKSINTNKCICLLSHWPFFEAFRKFLMFIYKLSVSGPHPLPIEKHISHFMQNIPFPS
  PQRPRILVQLSVHDALILSQPVSTPLPLSGANFSTLLMNLGPENCATLLLFVLLESKILL
  HSLRPAVLTGVAEAVVAMIFPFQWQCPYIPLCPLSLAAVLSAPLPFIVGVDSRYFDLHDP
  PQDVVCIDLDTNMLYVSDEKKNMNWKQLPKKPCKNLLSTLKKLYPQLSSVHQKTQEGSAI
  DMTPIEADFSWQKKMTQLEMEIQEAFLRFMASILKGYRTYLRPITEAPSNKATAADSLFD
  RQGFLKSRDRAYAKFYTLLSKTQIFIRFIEECSFVSDKDTGLAFFDDCIEKLFPDKGTEK
  TDKVDFDSAEDTRLIELDDSQKSEHTVFIMPPEPPPDDGKDLSPKYSYKYFPRLDLKLFD
  RPQELKLCFSRHPTGNSITKSPPLMAKRTKQEIKTAHKLAKRCYTNPPQWAKCLFSHCYS
  LWFICLPAYVRVSHPKVRALQQAYDVLIKMRKTDVDPLDEVCYRVVMQLCGLWGHPVLAV
  RVLFEMKTARIKPNAITYGYYNKVVLESPWPSSTRSGIFLWTKVRNVVRGLAQFRQPLKK
  TVQRSQVSSISGGQSDQGYGSKDELIKDDAEIHVPEEQAARELITKTKMQTEEVCDASAI
  VAKHSQPSPEPHSPTEPPAWGSSIVKVPSGIFDVNSRKSSTGSISNVLFSTQDPVEDAVF
  GEATNLKKNGDRGEKRQKHFPERSCSFSSESRAGMLLKKSSLDSNSSEMAIMMGADAKIL
  TAALTCPKTSLLHIARTHSFENVSCHLPDSRTCMSESTWNPEHRSSPVPEMLEESQELLE
  PVVDDVPKTTATVDTYESLLSDSNSNQSRDLKTVSKDLRNKRSSLYGIAKVVQREDVETG
  LDPLSLLATECTGGKTPDSEDKLFSPVIARNLADEIESYMNLKSPLGSKSSSMELHREEN
  RESGMTTAFIHALERRSSLPLDHGSPAQENPESEKSSPAVSRSKTFTGRFKQQTPSRTHK
  ERSTSLSALVRSSPHGSLGSVVNSLSGLKLDNILSGPKIDVLKSGMKQAATVASKMWVAV
  ASAYSYSDDEEETNRDYSFPAGLEDHILGENISPNTSISGLVPSELTQSNTSLGSSSSSG
  DVGKLHYPTGEVPFPRGMKGQDFEKSDHGSSQNTSMSSIYQNCAMEVLMSSCSQCRACGA
  LVYDEEIMAGWTADDSNLNTACPFCKSNFLPLLNIEFKDLRGSASFFLKPSTSGDSLQSG
  SIPLANESLEHKPVSSLAEPDLINFMDFPKHNQIITEETGSAVEPSDEIKRASGDVQTMK
  ISSVPNSLSKRNVSLTRSHSVGGPLQNIDFTQRPFHGISTVSLPNSLQEVVDPLGKRPNP
  PPVSVPYLSPLVLRKELESLLENEGDQVIHTSSFINQHPIIFWNLVWYFRRLDLPSNLPG
  LILTSEHCNEGVQLPLSSLSQDSKLVYIQLLWDNINLHQEPREPLYVSWRNFNSEKKSSL
  LSEEQQETSTLVETIRQSIQHNNVLKPINLLSQQMKPGMKRQRSLYREILFLSLVSLGRE
  NIDIEAFDNEYGIAYNSLSSEILERLQKIDAPPSASVEWCRKCFGAPLI
• Function: Guanine nucleotide exchange factor (GEF) activating RAB10. Promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB10 into its active GTP-bound form. Thereby, stimulates SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the plasma membrane in response to insulin.
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

10 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 DENN domain-containing protein 4C (DENND4C).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DENN domain-containing protein 4C (DENND4C).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DENN domain-containing protein 4C (DENND4C).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of DENN domain-containing protein 4C (DENND4C).	[4]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of DENN domain-containing protein 4C (DENND4C).	[5]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of DENN domain-containing protein 4C (DENND4C).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DENN domain-containing protein 4C (DENND4C).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of DENN domain-containing protein 4C (DENND4C).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DENN domain-containing protein 4C (DENND4C).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DENN domain-containing protein 4C (DENND4C).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DENN domain-containing protein 4C (DENND4C).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DENN domain-containing protein 4C (DENND4C).	[9]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [4] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [5] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [6] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [7] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [8] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] 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.
• [10] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.