Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB51VKY)

• DOT Name: SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C)
• Synonyms: SLIT-ROBO Rho GTPase activating protein 2 pseudogene 1
• Gene Name: SRGAP2C
• UniProt ID: SRG2C_HUMAN
• Pfam ID: PF00611
• Sequence:
  MTSPAKFKKDKEIIAEYDTQVKEIRAQLTEQMKCLDQQCELRVQLLQDLQDFFRKKAEIE
  MDYSRNLEKLAEHFLAKTRSTKDQQFKKDQNVLSPVNCWNLLLNQVKWESRDHTTLSDIY
  LNNIIPRFVQVSEDSGRLFKKSKEVGQQLQDDLMKVLNELYSVMKTYHMYNADSISAQSK
  LKEAEKQEEKQIGKSVKQEDRQTPCSPDSTANVRIEEKHVRRSSVKKIEKMKEKHQAKYT
  ENKLKAIKAQNEYLLALEATNASVFKYYIHDLSDLIDQCCDLGYHASLNRALRTFLSAEL
  NLEQSKHEGLDAIENAVENLDATSDKQRLMEMYNNVFCPPMKFEFQPHMGDMASQLCAQQ
  PVQSELVQRCQQLQSRLSTLKIENEEVKKTMEATLQTIQDIVTVEDFDVSDCFQYSNSME
  SVKSTVSETFMSKPSIAKRRANQQETEQFYFTVRECYGF
• Function: Human-specific protein that acts as a key modifier of cortical connectivity in the human brain. Acts by inhibiting the functions of ancestral paralog SRGAP2/SRGAP2A, a postsynaptic protein that regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons. SRGAP2C is unstable but is able to heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation. Inhibition of SRGAP2/SRGAP2A by SRGAP2C leads to an increase in synaptic density and protracted synaptic maturation of both excitatory and inhibitory synapses. Modifies cortical circuit connectivity by increasing the number of local and long-range cortical inputs received by layer 2/3 pyramidal neurons. Also able to increase the probability of sensory-evoked responses by layer 2/3 pyramidal neurons.
• Tissue Specificity: Ubiquitously expressed with higher expression in cerebellum . Probably expressed in fetal and adult neurons (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C).	[3]
Marinol	DM70IK5	Approved	Marinol increases the expression of SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C).	[4]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C).	[6]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of SLIT-ROBO Rho GTPase-activating protein 2C (SRGAP2C).	[7]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [2] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [5] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [6] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.