Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSPBZ4Z)

• DOT Name: MOB kinase activator 1A (MOB1A)
• Synonyms: Mob1 alpha; Mob1A; Mob1 homolog 1B; Mps one binder kinase activator-like 1B
• Gene Name: MOB1A
• Related Disease:
  Lung neoplasm
  Non-small-cell lung cancer
  Advanced cancer
  Colorectal carcinoma
  Intrahepatic cholangiocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Obesity
  Renal fibrosis
  Colon cancer
  Colorectal neoplasm
• UniProt ID: MOB1A_HUMAN
• PDB ID: 1PI1; 4J1V; 4JIZ; 5BRK; 5BRM; 5TWF; 5TWG; 5TWH; 5XQZ; 6MCP; 6MCQ
• Pfam ID: PF03637
• Sequence:
  MSFLFSSRSSKTFKPKKNIPEGSHQYELLKHAEATLGSGNLRQAVMLPEGEDLNEWIAVN
  TVDFFNQINMLYGTITEFCTEASCPVMSAGPRYEYHWADGTNIKKPIKCSAPKYIDYLMT
  WVQDQLDDETLFPSKIGVPFPKNFMSVAKTILKRLFRVYAHIYHQHFDSVMQLQEEAHLN
  TSFKHFIFFVQEFNLIDRRELAPLQELIEKLGSKDR
• Function: Activator of LATS1/2 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. Stimulates the kinase activity of STK38 and STK38L. Acts cooperatively with STK3/MST2 to activate STK38.
• Tissue Specificity: Adrenal gland, bone marrow, brain, placenta, prostate, salivary gland, skeletal muscle, testis, thymus, thyroid gland, heart, spinal cord, fetal brain and fetal liver.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway: Signaling by Hippo (R-HSA-2028269)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung neoplasm	DISVARNB	Definitive	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Limited	Altered Expression	[3]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[3]

1 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 MOB kinase activator 1A (MOB1A).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MOB kinase activator 1A (MOB1A).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of MOB kinase activator 1A (MOB1A).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of MOB kinase activator 1A (MOB1A).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of MOB kinase activator 1A (MOB1A).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of MOB kinase activator 1A (MOB1A).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of MOB kinase activator 1A (MOB1A).	[15]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of MOB kinase activator 1A (MOB1A).	[16]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of MOB kinase activator 1A (MOB1A).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of MOB kinase activator 1A (MOB1A).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of MOB kinase activator 1A (MOB1A).	[19]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of MOB kinase activator 1A (MOB1A).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of MOB kinase activator 1A (MOB1A).	[17]

References

• [1] Human MOB1 expression in non-small-cell lung cancer.Clin Lung Cancer. 2007 Jan;8(4):273-6. doi: 10.3816/CLC.2007.n.006.
• [2] Cancer susceptibility and embryonic lethality in Mob1a/1b double-mutant mice.J Clin Invest. 2012 Dec;122(12):4505-18. doi: 10.1172/JCI63735. Epub 2012 Nov 12.
• [3] Clinical significance of the loss of MATS1 mRNA expression in colorectal cancer.Int J Oncol. 2007 Aug;31(2):333-8.
• [4] Altered Expression of Hippo Signaling Pathway Molecules in Intrahepatic Cholangiocarcinoma.Oncology. 2017;93(1):67-74. doi: 10.1159/000463390. Epub 2017 Apr 28.
• [5] MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation.Oncogene. 2017 Jul 20;36(29):4201-4211. doi: 10.1038/onc.2017.58. Epub 2017 Mar 27.
• [6] Stable MOB1 interaction with Hippo/MST is not essential for development and tissue growth control.Nat Commun. 2017 Sep 25;8(1):695. doi: 10.1038/s41467-017-00795-y.
• [7] Genetic modifiers of Leprfa associated with variability in insulin production and susceptibility to NIDDM.Genomics. 1997 May 1;41(3):332-44. doi: 10.1006/geno.1997.4672.
• [8] Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1.Cell Rep. 2019 Dec 10;29(11):3664-3677.e5. doi: 10.1016/j.celrep.2019.11.035.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] 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.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] 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.
• [15] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [16] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [17] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [19] 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.
• [20] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.