Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9GUVLI)

• DOT Name: Kinase suppressor of Ras 1 (KSR1)
• Synonyms: EC 2.7.11.1
• Gene Name: KSR1
• UniProt ID: KSR1_HUMAN
• PDB ID: 5VYK; 7JUW; 7JUX; 7JUY; 7JUZ; 7JV0; 7JV1
• EC Number: 2.7.11.1
• Pfam ID: PF07714 ; PF20406
• Sequence:
  MDRAALRAAAMGEKKEGGGGGDAAAAEGGAGAAASRALQQCGQLQKLIDISIGSLRGLRT
  KCAVSNDLTQQEIRTLEAKLVRYICKQRQCKLSVAPGERTPELNSYPRFSDWLYTFNVRP
  EVVQEIPRDLTLDALLEMNEAKVKETLRRCGASGDECGRLQYALTCLRKVTGLGGEHKED
  SSWSSLDARRESGSGPSTDTLSAASLPWPPGSSQLGRAGNSAQGPRSISVSALPASDSPT
  PSFSEGLSDTCIPLHASGRLTPRALHSFITPPTTPQLRRHTKLKPPRTPPPPSRKVFQLL
  PSFPTLTRSKSHESQLGNRIDDVSSMRFDLSHGSPQMVRRDIGLSVTHRFSTKSWLSQVC
  HVCQKSMIFGVKCKHCRLKCHNKCTKEAPACRISFLPLTRLRRTESVPSDINNPVDRAAE
  PHFGTLPKALTKKEHPPAMNHLDSSSNPSSTTSSTPSSPAPFPTSSNPSSATTPPNPSPG
  QRDSRFNFPAAYFIHHRQQFIFPVPSAGHCWKCLLIAESLKENAFNISAFAHAAPLPEAA
  DGTRLDDQPKADVLEAHEAEAEEPEAGKSEAEDDEDEVDDLPSSRRPWRGPISRKASQTS
  VYLQEWDIPFEQVELGEPIGQGRWGRVHRGRWHGEVAIRLLEMDGHNQDHLKLFKKEVMN
  YRQTRHENVVLFMGACMNPPHLAIITSFCKGRTLHSFVRDPKTSLDINKTRQIAQEIIKG
  MGYLHAKGIVHKDLKSKNVFYDNGKVVITDFGLFGISGVVREGRRENQLKLSHDWLCYLA
  PEIVREMTPGKDEDQLPFSKAADVYAFGTVWYELQARDWPLKNQAAEASIWQIGSGEGMK
  RVLTSVSLGKEVSEILSACWAFDLQERPSFSLLMDMLEKLPKLNRRLSHPGHFWKSADIN
  SSKVVPRFERFGLGVLESSNPKM
• Function: Part of a multiprotein signaling complex which promotes phosphorylation of Raf family members and activation of downstream MAP kinases. Independently of its kinase activity, acts as MAP2K1/MEK1 and MAP2K2/MEK2-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1 or MAP2K2/MEK2, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 and/or MAP2K2/MEK2. Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP. Its kinase activity is unsure. Some protein kinase activity has been detected in vitro, however the physiological relevance of this activity is unknown.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  MAP2K and MAPK activation (R-HSA-5674135)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  RAF activation (R-HSA-5673000)

Molecular Interaction Atlas (MIA) of This DOT

3 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 Kinase suppressor of Ras 1 (KSR1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Kinase suppressor of Ras 1 (KSR1).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Kinase suppressor of Ras 1 (KSR1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kinase suppressor of Ras 1 (KSR1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kinase suppressor of Ras 1 (KSR1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kinase suppressor of Ras 1 (KSR1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kinase suppressor of Ras 1 (KSR1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kinase suppressor of Ras 1 (KSR1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Kinase suppressor of Ras 1 (KSR1).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Kinase suppressor of Ras 1 (KSR1).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Kinase suppressor of Ras 1 (KSR1).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Kinase suppressor of Ras 1 (KSR1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Kinase suppressor of Ras 1 (KSR1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kinase suppressor of Ras 1 (KSR1).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Kinase suppressor of Ras 1 (KSR1).	[15]

References

• [1] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
• [7] Quercetin and Cisplatin combined treatment altered cell cycle and mitogen activated protein kinase expressions in malignant mesotelioma cells. BMC Complement Altern Med. 2016 Aug 11;16(1):281. doi: 10.1186/s12906-016-1267-x.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] 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.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.