Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT88N84O)

• DOT Name: Helix-loop-helix protein 2 (NHLH2)
• Synonyms: HEN-2; Class A basic helix-loop-helix protein 34; bHLHa34; Nescient helix loop helix 2; NSCL-2
• Gene Name: NHLH2
• Related Disease:
  Hypogonadism
  Prader-Willi syndrome
  Hypogonadotropic hypogonadism 27 without anosmia
  Neoplasm
  Neuroblastoma
  Obesity
• UniProt ID: HEN2_HUMAN
• Pfam ID: PF00010
• Sequence:
  MMLSPDQAADSDHPSSAHSDPESLGGTDTKVLGSVSDLEPVEEAEGDGKGGSRAALYPHP
  QQLSREEKRRRRRATAKYRSAHATRERIRVEAFNLAFAELRKLLPTLPPDKKLSKIEILR
  LAICYISYLNHVLDV
• Function: Transcription factor which binds the E box motif 5'-CA[TC][AG]TG-3'. Involved in regulating energy expenditure, body mass, voluntary physical activity, mating behavior and reproductive longevity, acting through the hypothalamic-pituitary-gonadal axis. Acts as a transcriptional activator of target genes, including NDN, PCSK1, MC4R. Is also a transcriptional activator of KISS1. May act centrally to regulate function of both white and brown adipose tissue. Together with NHLH1, required to maintain migration and survival of cells in the anterior extramural migration stream (aes), which forms the precerebellar nuclei. Also, in concert with NHLH1, may determine fate of gonadotropin releasing hormone-1 (GnRH-1) neurons.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadism	DISICMNI	Strong	Biomarker	[1]
Prader-Willi syndrome	DISYWMLU	Strong	Biomarker	[2]
Hypogonadotropic hypogonadism 27 without anosmia	DIS1I4BY	Limited	Unknown	[3]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[5]
Obesity	DIS47Y1K	Limited	Biomarker	[1]

4 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 Helix-loop-helix protein 2 (NHLH2).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Helix-loop-helix protein 2 (NHLH2).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Helix-loop-helix protein 2 (NHLH2).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Helix-loop-helix protein 2 (NHLH2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Helix-loop-helix protein 2 (NHLH2).	[9]

References

• [1] Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome.J Clin Invest. 2017 Jan 3;127(1):293-305. doi: 10.1172/JCI88648. Epub 2016 Dec 12.
• [2] Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome.J Clin Invest. 2018 Mar 1;128(3):960-969. doi: 10.1172/JCI97007. Epub 2018 Jan 29.
• [3] Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans. Hum Genet. 2022 Feb;141(2):295-304. doi: 10.1007/s00439-021-02422-9. Epub 2022 Jan 23.
• [4] LMO3 interacts with neuronal transcription factor, HEN2, and acts as an oncogene in neuroblastoma.Cancer Res. 2005 Jun 1;65(11):4587-97. doi: 10.1158/0008-5472.CAN-04-4630.
• [5] NHLH2: at the intersection of obesity and fertility.Trends Endocrinol Metab. 2013 Aug;24(8):385-90. doi: 10.1016/j.tem.2013.04.003. Epub 2013 May 17.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.