Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4PKH8L)

• DOT Name: NFAT activation molecule 1 (NFAM1)
• Synonyms: Calcineurin/NFAT-activating ITAM-containing protein; NFAT-activating protein with ITAM motif 1
• Gene Name: NFAM1
• Related Disease:
  Advanced cancer
  Bone Paget disease
• UniProt ID: NFAM1_HUMAN
• Sequence:
  MENQPVRWRALPGLPRPPGLPAAPWLLLGVLLLPGTLRLAGGQSVTHTGLPIMASLANTA
  ISFSCRITYPYTPQFKVFTVSYFHEDLQGQRSPKKPTNCHPGLGTENQSHTLDCQVTLVL
  PGASATGTYYCSVHWPHSTVRGSGTFILVRDAGYREPPQSPQKLLLFGFTGLLSVLSVVG
  TALLLWNKKRMRGPGKDPTRKCPDPRSASSPKQHPSESVYTALQRRETEVYACIENEDGS
  SPTAKQSPLSQERPHRFEDDGELNLVYENL
• Function: May function in immune system as a receptor which activates via the calcineurin/NFAT-signaling pathway the downstream cytokine gene promoters. Activates the transcription of IL-13 and TNF-alpha promoters. May be involved in the regulation of B-cell, but not T-cell, development. Overexpression activates downstream effectors without ligand binding or antibody cross-linking.
• Tissue Specificity: Highly expressed in neutrophils, primary monocytes, mast cells, monocytic cell lines and lymphocytes. Also expressed in spleen B and T-cells, and lung. Expressed at low level in non-immune tissue.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Bone Paget disease	DISIPS4V	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NFAT activation molecule 1 (NFAM1).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of NFAT activation molecule 1 (NFAM1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NFAT activation molecule 1 (NFAM1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of NFAT activation molecule 1 (NFAM1).	[8]

2 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 NFAT activation molecule 1 (NFAM1).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of NFAT activation molecule 1 (NFAM1).	[7]

References

• [1] Pirin: a potential novel therapeutic target for castration-resistant prostate cancer regulated by miR-455-5p.Mol Oncol. 2019 Feb;13(2):322-337. doi: 10.1002/1878-0261.12405. Epub 2018 Dec 21.
• [2] NFAM1 signaling enhances osteoclast formation and bone resorption activity in Paget's disease of bone.Bone. 2017 Aug;101:236-244. doi: 10.1016/j.bone.2017.05.013. Epub 2017 May 12.
• [3] 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.
• [4] 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.
• [5] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [6] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [7] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [8] 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.