Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ0VFDL)

• DOT Name: Programmed cell death 1 ligand 1 (CD274)
• Synonyms: PD-L1; PDCD1 ligand 1; Programmed death ligand 1; hPD-L1; B7 homolog 1; B7-H1; CD antigen CD274
• Gene Name: CD274
• Related Disease: Neonatal diabetes mellitus
• UniProt ID: PD1L1_HUMAN
• PDB ID: 3BIK ; 3BIS ; 3FN3 ; 3SBW ; 4Z18 ; 4ZQK ; 5C3T ; 5GGT ; 5GRJ ; 5IUS ; 5J89 ; 5J8O ; 5JDR ; 5JDS ; 5N2D ; 5N2F ; 5NIU ; 5O45 ; 5O4Y ; 5X8L ; 5X8M ; 5XJ4 ; 5XXY ; 6L8R ; 6NM7 ; 6NM8 ; 6NNV ; 6NOJ ; 6NOS ; 6NP9 ; 6PV9 ; 6R3K ; 6RPG ; 6VQN ; 6YCR ; 7BEA ; 7C88 ; 7CZD ; 7DCV ; 7DY7 ; 7NLD ; 7OUN ; 7SJQ ; 7TPS ; 7UX5 ; 7UXO ; 7UXP ; 7UXQ ; 7VUN ; 7XAD ; 7XAE ; 7YDS ; 8ALX ; 8AOK ; 8AOM ; 8JBA ; 8OR1
• Pfam ID: PF08205 ; PF07686
• Sequence:
  MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEME
  DKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGG
  ADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTT
  TTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTH
  LVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET
• Function: Plays a critical role in induction and maintenance of immune tolerance to self. As a ligand for the inhibitory receptor PDCD1/PD-1, modulates the activation threshold of T-cells and limits T-cell effector response. Through a yet unknown activating receptor, may costimulate T-cell subsets that predominantly produce interleukin-10 (IL10). Can also act as a transcription coactivator: in response to hypoxia, translocates into the nucleus via its interaction with phosphorylated STAT3 and promotes transcription of GSDMC, leading to pyroptosis ; The PDCD1-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival. The interaction with PDCD1/PD-1 inhibits cytotoxic T lymphocytes (CTLs) effector function. The blockage of the PDCD1-mediated pathway results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy.
• Tissue Specificity: Highly expressed in the heart, skeletal muscle, placenta and lung. Weakly expressed in the thymus, spleen, kidney and liver. Expressed on activated T- and B-cells, dendritic cells, keratinocytes and monocytes.; [Isoform 4]: Widely expressed, highest in lung, liver and pituitary and in various peripheral blood cells, including neutrophils and some subtypes of lymphoid and myeloid cells.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  STAT3 nuclear events downstream of ALK signaling (R-HSA-9701898)
  PD-1 signaling (R-HSA-389948)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neonatal diabetes mellitus	DISFHF9K	Limited	Autosomal recessive	[1]

1 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 Programmed cell death 1 ligand 1 (CD274).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Programmed cell death 1 ligand 1 (CD274).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Programmed cell death 1 ligand 1 (CD274).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Programmed cell death 1 ligand 1 (CD274).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Programmed cell death 1 ligand 1 (CD274).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Programmed cell death 1 ligand 1 (CD274).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Programmed cell death 1 ligand 1 (CD274).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Programmed cell death 1 ligand 1 (CD274).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[13]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Programmed cell death 1 ligand 1 (CD274).	[14]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Programmed cell death 1 ligand 1 (CD274).	[10]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Programmed cell death 1 ligand 1 (CD274).	[10]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[15]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Programmed cell death 1 ligand 1 (CD274).	[16]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[17]
Sevoflurane	DMC9O43	Approved	Sevoflurane decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Programmed cell death 1 ligand 1 (CD274).	[19]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[20]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Programmed cell death 1 ligand 1 (CD274).	[21]
MGCD-0103	DM726HX	Phase 2	MGCD-0103 increases the expression of Programmed cell death 1 ligand 1 (CD274).	[11]
PF-4878691	DM24I0N	Phase 2	PF-4878691 increases the expression of Programmed cell death 1 ligand 1 (CD274).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Programmed cell death 1 ligand 1 (CD274).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[25]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Programmed cell death 1 ligand 1 (CD274).	[27]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Programmed cell death 1 ligand 1 (CD274).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Programmed cell death 1 ligand 1 (CD274).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Programmed cell death 1 ligand 1 (CD274).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Programmed cell death 1 ligand 1 (CD274).	[31]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Programmed cell death 1 ligand 1 (CD274).	[32]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Programmed cell death 1 ligand 1 (CD274).	[33]
PD98059	DMZC90M	Investigative	PD98059 decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[26]
L-thyroxine	DM83HWL	Investigative	L-thyroxine increases the expression of Programmed cell death 1 ligand 1 (CD274).	[26]
nexturastat A	DM6NS7H	Investigative	nexturastat A decreases the expression of Programmed cell death 1 ligand 1 (CD274).	[11]

References

• [1] 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.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest. 2011 Aug;121(8):3100-8. doi: 10.1172/JCI43656. Epub 2011 Jul 18.
• [7] Oxidative stress modulates expression of immune checkpoint genes via activation of AhR signaling. Toxicol Appl Pharmacol. 2022 Dec 15;457:116314. doi: 10.1016/j.taap.2022.116314. Epub 2022 Nov 9.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol. 2008 Mar;45(5):1470-6. doi: 10.1016/j.molimm.2007.08.013. Epub 2007 Oct 24.
• [11] Essential role of HDAC6 in the regulation of PD-L1 in?melanoma. Mol Oncol. 2016 May;10(5):735-750. doi: 10.1016/j.molonc.2015.12.012. Epub 2016 Jan 6.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] The anthelmintic drug niclosamide induces GSK--mediated -catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression. Cell Death Dis. 2022 Feb 3;13(2):112. doi: 10.1038/s41419-022-04573-7.
• [14] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [15] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] Thalidomide suppresses angiogenesis and immune evasion via lncRNA FGD5-AS1/miR-454-3p/ZEB1 axis-mediated VEGFA expression and PD-1/PD-L1 checkpoint in NSCLC. Chem Biol Interact. 2021 Nov 1;349:109652. doi: 10.1016/j.cbi.2021.109652. Epub 2021 Sep 11.
• [18] CircRNA VIM silence synergizes with sevoflurane to inhibit immune escape and multiple oncogenic activities of esophageal cancer by simultaneously regulating miR-124/PD-L1 axis. Cell Biol Toxicol. 2022 Oct;38(5):825-845. doi: 10.1007/s10565-021-09613-0. Epub 2021 May 20.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Autophagy inhibition upregulates CD4(+) tumor infiltrating lymphocyte expression via miR-155 regulation and TRAIL activation. Mol Oncol. 2016 Dec;10(10):1516-1531. doi: 10.1016/j.molonc.2016.08.005. Epub 2016 Sep 16.
• [21] Characterization of reconstructed human skin containing Langerhans cells to monitor molecular events in skin sensitization. Toxicol In Vitro. 2018 Feb;46:77-85. doi: 10.1016/j.tiv.2017.09.019. Epub 2017 Sep 21.
• [22] Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation. Antimicrob Agents Chemother. 2010 Feb;54(2):871-81. doi: 10.1128/AAC.01246-09. Epub 2009 Nov 30.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] 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.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] Nano-diamino-tetrac (NDAT) inhibits PD-L1 expression which is essential for proliferation in oral cancer cells. Food Chem Toxicol. 2018 Oct;120:1-11. doi: 10.1016/j.fct.2018.06.058. Epub 2018 Jun 28.
• [27] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [28] Evaluation of selected biomarkers for the detection of chemical sensitization in human skin: a comparative study applying THP-1, MUTZ-3 and primary dendritic cells in culture. Toxicol In Vitro. 2013 Sep;27(6):1659-69. doi: 10.1016/j.tiv.2013.04.009. Epub 2013 Apr 26.
• [29] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [30] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [32] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [33] Identification of PDL-1 as a novel biomarker of sensitizer exposure in dendritic-like cells. Toxicol In Vitro. 2010 Sep;24(6):1727-35. doi: 10.1016/j.tiv.2010.05.008. Epub 2010 May 19.