Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6752M0)

• DOT Name: Inactive Rho GTPase-activating protein 11B (ARHGAP11B)
• Synonyms: Rho-type GTPase-activating protein 11B
• Gene Name: ARHGAP11B
• Related Disease: Schizophrenia
• UniProt ID: RHGBB_HUMAN
• Pfam ID: PF00620
• Sequence:
  MWDQRLVKLALLQHLRAFYGIKVKGVRGQCDRRRHETAATEIGGKIFGVPFNALPHSAVP
  EYGHIPSFLVDACTSLEEHIHTEGLFRKSGSVIRLKALKNKVDHGEGCLSSAPPCDIAGL
  LKQFFRELPEPILPADLHEALLKAQQLGTEEKNKAILLLSCLLADHTVHVLRYFFNFLRN
  VSLRSSENKMDSSNLAVIFAPNLLQTSEGHEKMSSNAEKKGVYQTLSWKRYQPCWVLMVS
  VLLHHWKALKKVNMKLLVNIREREDNV
• Function: Hominin-specific protein that promotes development and evolutionary expansion of the brain neocortex. Able to promote amplification of basal progenitors in the subventricular zone, producing more neurons during fetal corticogenesis, thereby playing a key role in neocortex expansion. Promotes the proliferation of basal progenitors by inhibiting the mitochondrial permeability transition pore (mPTP): delays the opening of the mPTP via interaction with ADP:ATP translocase, thereby increasing mitochondrial Ca(2+) concentration and inducing glutamine catabolism, which is required for basal progenitor proliferation. Does not possess GTPase activator activity: the absence of GTPase activator activity is required to promote amplification of basal progenitors during neocortex development.
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inactive Rho GTPase-activating protein 11B (ARHGAP11B).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Inactive Rho GTPase-activating protein 11B (ARHGAP11B).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Inactive Rho GTPase-activating protein 11B (ARHGAP11B).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Inactive Rho GTPase-activating protein 11B (ARHGAP11B).	[4]
Marinol	DM70IK5	Approved	Marinol increases the expression of Inactive Rho GTPase-activating protein 11B (ARHGAP11B).	[5]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Inactive Rho GTPase-activating protein 11B (ARHGAP11B).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inactive Rho GTPase-activating protein 11B (ARHGAP11B).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inactive Rho GTPase-activating protein 11B (ARHGAP11B).	[8]

References

• [1] De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes. Eur J Hum Genet. 2019 Jul;27(7):1121-1133. doi: 10.1038/s41431-019-0376-7. Epub 2019 Mar 18.
• [2] 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.
• [3] 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.
• [4] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [5] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [6] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [7] 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.
• [8] 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.