Details of Drug Off-Target (DOT)

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

• DOT Name: Male-specific lethal 1 homolog (MSL1)
• Synonyms: MSL-1; Male-specific lethal 1-like 1; MSL1-like 1; Male-specific lethal-1 homolog 1
• Gene Name: MSL1
• Related Disease: Advanced cancer
• UniProt ID: MSL1_HUMAN
• PDB ID: 4B7Y; 4B86; 4DNC
• Pfam ID: PF16801 ; PF15275
• Sequence:
  MTMRSAVFKAAAAPAGGNPEQRLDYERAAALGGPEDEPGAAEAHFLPRHRKLKEPGPPLA
  SSQGGSPAPSPAGCGGKGRGLLLPAGAAPGQQEESWGGSVPLPCPPPATKQAGIGGEPAA
  AGAGCSPRPKYQAVLPIQTGSLVAAAKEPTPWAGDKGGAASPAATASDPAGPPPLPLPGP
  PPLAPTATAGTLAASEGRWKSMRKSPLGGGGGSGASSQAACLKQILLLQLDLIEQQQQQL
  QAKEKEIEELKSERDTLLARIERMERRMQLVKKDNEKERHKLFQGYETEEREETELSEKI
  KLECQPELSETSQTLPPKPFSCGRSGKGHKRKSPFGSTERKTPVKKLAPEFSKVKTKTPK
  HSPIKEEPCGSLSETVCKRELRSQETPEKPRSSVDTPPRLSTPQKGPSTHPKEKAFSSEI
  EDLPYLSTTEMYLCRWHQPPPSPLPLRESSPKKEETVARCLMPSSVAGETSVLAVPSWRD
  HSVEPLRDPNPSDLLENLDDSVFSKRHAKLELDEKRRKRWDIQRIREQRILQRLQLRMYK
  KKGIQESEPEVTSFFPEPDDVESLMITPFLPVVAFGRPLPKLTPQNFELPWLDERSRCRL
  EIQKKQTPHRTCRK
• Function: Component of histone acetyltransferase complex responsible for the majority of histone H4 acetylation at 'Lys-16' (H4K16ac) which is implicated in the formation of higher-order chromatin structure. Greatly enhances MSL2 E3 ubiquitin ligase activity, promoting monoubiquitination of histone H2B at 'Lys-34' (H2BK34Ub). This modification in turn stimulates histone H3 methylation at 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) and leads to gene activation, including that of HOXA9 and MEIS1. In the MSL complex, acts as a scaffold to tether MSL3 and KAT8 together for enzymatic activity regulation.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]

11 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 Male-specific lethal 1 homolog (MSL1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Male-specific lethal 1 homolog (MSL1).	[3]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Male-specific lethal 1 homolog (MSL1).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Male-specific lethal 1 homolog (MSL1).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the expression of Male-specific lethal 1 homolog (MSL1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Male-specific lethal 1 homolog (MSL1).	[8]
Scriptaid	DM9JZ21	Preclinical	Scriptaid decreases the expression of Male-specific lethal 1 homolog (MSL1).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Male-specific lethal 1 homolog (MSL1).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Male-specific lethal 1 homolog (MSL1).	[11]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Male-specific lethal 1 homolog (MSL1).	[12]
Apicidin	DM83WVF	Investigative	Apicidin decreases the expression of Male-specific lethal 1 homolog (MSL1).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Male-specific lethal 1 homolog (MSL1).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Male-specific lethal 1 homolog (MSL1).	[9]

References

• [1] Risk of ovarian cancer and inherited variants in relapse-associated genes.PLoS One. 2010 Jan 27;5(1):e8884. doi: 10.1371/journal.pone.0008884.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [7] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [8] 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.
• [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] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.