Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT78QCN8)

DOT Name	GTPase KRas (KRAS)
Synonyms	EC 3.6.5.2; K-Ras 2; Ki-Ras; c-K-ras; c-Ki-ras
Gene Name	KRAS
Related Disease	Cardiofaciocutaneous syndrome 1 ( ) Cardiofaciocutaneous syndrome 2 ( ) Noonan syndrome ( ) Noonan syndrome 3 ( ) Cardiofaciocutaneous syndrome ( ) Linear nevus sebaceous syndrome ( ) Costello syndrome ( )
UniProt ID	RASK_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1D8D ; 1D8E ; 1KZO ; 1KZP ; 1N4P ; 1N4Q ; 1N4R ; 1N4S ; 3GFT ; 4DSN ; 4DSO ; 4EPR ; 4EPT ; 4EPV ; 4EPW ; 4EPX ; 4EPY ; 4L8G ; 4LDJ ; 4LPK ; 4LRW ; 4LUC ; 4LV6 ; 4LYF ; 4LYH ; 4LYJ ; 4M1O ; 4M1S ; 4M1T ; 4M1W ; 4M1Y ; 4M21 ; 4M22 ; 4NMM ; 4OBE ; 4PZY ; 4PZZ ; 4Q01 ; 4Q02 ; 4Q03 ; 4QL3 ; 4TQ9 ; 4TQA ; 4WA7 ; 5F2E ; 5KYK ; 5MLA ; 5MLB ; 5O2S ; 5O2T ; 5OCG ; 5OCO ; 5OCT ; 5TAR ; 5TB5 ; 5UFE ; 5UFQ ; 5UK9 ; 5UQW ; 5US4 ; 5USJ ; 5V6S ; 5V6V ; 5V71 ; 5V9L ; 5V9O ; 5V9U ; 5VBM ; 5VP7 ; 5VPI ; 5VPY ; 5VPZ ; 5VQ0 ; 5VQ1 ; 5VQ2 ; 5VQ6 ; 5VQ8 ; 5W22 ; 5WHA ; 5WHB ; 5WHD ; 5WHE ; 5WLB ; 5WPM ; 5XCO ; 5YXZ ; 5YY1 ; 6ARK ; 6ASA ; 6ASE ; 6B0V ; 6B0Y ; 6BOF ; 6BP1 ; 6CC9 ; 6CCH ; 6CCX ; 6CU6 ; 6E6F ; 6E6G ; 6EPL ; 6EPM ; 6EPN ; 6EPO ; 6EPP ; 6F76 ; 6FA1 ; 6FA2 ; 6FA3 ; 6FA4 ; 6GJ5 ; 6GJ6 ; 6GJ7 ; 6GJ8 ; 6GOD ; 6GOE ; 6GOF ; 6GOG ; 6GOM ; 6GQT ; 6GQW ; 6GQX ; 6GQY ; 6H46 ; 6H47 ; 6JTN ; 6JTO ; 6JTP ; 6M9W ; 6MBQ ; 6MBT ; 6MBU ; 6MNX ; 6MQG ; 6MQN ; 6MS9 ; 6MTA ; 6N2J ; 6N2K ; 6O36 ; 6O46 ; 6O4Y ; 6O4Z ; 6O51 ; 6O53 ; 6OB2 ; 6OB3 ; 6OIM ; 6P0Z ; 6P8W ; 6P8X ; 6P8Y ; 6P8Z ; 6PGO ; 6PGP ; 6PQ3 ; 6PTS ; 6PTW ; 6QUU ; 6QUV ; 6QUW ; 6QUX ; 6T5B ; 6T5U ; 6T5V ; 6TAM ; 6TAN ; 6USX ; 6USZ ; 6UT0 ; 6V5L ; 6V65 ; 6V6F ; 6VC8 ; 6VJJ ; 6W4E ; 6W4F ; 6WGN ; 6WS2 ; 6WS4 ; 6XGU ; 6XGV ; 6XHA ; 6XHB ; 6YR8 ; 6YXW ; 6ZL5 ; 6ZLI ; 7A1W ; 7A1X ; 7A1Y ; 7A47 ; 7ACA ; 7ACF ; 7ACH ; 7ACQ ; 7C40 ; 7C41 ; 7EW9 ; 7EWA ; 7EWB ; 7EYX ; 7F0W ; 7KFZ ; 7KMR ; 7KYZ ; 7LC1 ; 7LC2 ; 7LGI ; 7LZ5 ; 7MDP ; 7MQU ; 7NY8 ; 7O70 ; 7OK3 ; 7OK4 ; 7OO7 ; 7Q9U ; 7R0M ; 7R0N ; 7R0Q ; 7ROV ; 7RP2 ; 7RP3 ; 7RP4 ; 7RPZ ; 7RSC ; 7RSE ; 7RT1 ; 7RT2 ; 7RT3 ; 7RT4 ; 7RT5 ; 7SCW ; 7SCX ; 7STF ; 7T1F ; 7T47 ; 7TLE ; 7TLG ; 7TLK ; 7U8H ; 7VVB ; 7W5R ; 7YCC ; 7YCE ; 7YUZ ; 7YV1 ; 8AFB ; 8AFC ; 8AFD ; 8AQ5 ; 8AQ7 ; 8AZR ; 8AZV ; 8AZX ; 8AZY ; 8AZZ ; 8B00 ; 8B6I ; 8B78 ; 8CX5 ; 8DNI ; 8DNJ ; 8DNK ; 8DVG ; 8EBZ ; 8ECR ; 8EDY ; 8EER ; 8EIE ; 8EPW ; 8EZG ; 8F0M ; 8FMJ ; 8FMK ; 8G42 ; 8G47 ; 8G4F ; 8G4H ; 8G9P ; 8G9Q ; 8I5E ; 8JJS ; 8ONV ; 8QU8 ; 8QUG ; 8QVU ; 8QW6 ; 8QW7 ; 8STM ; 8STN ; 8TXE ; 8TXG ; 8TXH
EC Number	3.6.5.2
Pfam ID	PF00071
Sequence	MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG QEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDL PSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGC VKIKKCIIM
Function	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation. Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner.
KEGG Pathway	EGFR tyrosine ki.se inhibitor resistance (hsa01521 ) Endocrine resistance (hsa01522 ) MAPK sig.ling pathway (hsa04010 ) ErbB sig.ling pathway (hsa04012 ) Ras sig.ling pathway (hsa04014 ) Rap1 sig.ling pathway (hsa04015 ) Chemokine sig.ling pathway (hsa04062 ) FoxO sig.ling pathway (hsa04068 ) Sphingolipid sig.ling pathway (hsa04071 ) Phospholipase D sig.ling pathway (hsa04072 ) Mitophagy - animal (hsa04137 ) Autophagy - animal (hsa04140 ) mTOR sig.ling pathway (hsa04150 ) PI3K-Akt sig.ling pathway (hsa04151 ) Apoptosis (hsa04210 ) Longevity regulating pathway (hsa04211 ) Longevity regulating pathway - multiple species (hsa04213 ) Cellular senescence (hsa04218 ) Axon guidance (hsa04360 ) VEGF sig.ling pathway (hsa04370 ) Apelin sig.ling pathway (hsa04371 ) Gap junction (hsa04540 ) Sig.ling pathways regulating pluripotency of stem cells (hsa04550 ) C-type lectin receptor sig.ling pathway (hsa04625 ) .tural killer cell mediated cytotoxicity (hsa04650 ) T cell receptor sig.ling pathway (hsa04660 ) B cell receptor sig.ling pathway (hsa04662 ) Fc epsilon RI sig.ling pathway (hsa04664 ) Thermogenesis (hsa04714 ) Long-term potentiation (hsa04720 ) Neurotrophin sig.ling pathway (hsa04722 ) Cholinergic sy.pse (hsa04725 ) Serotonergic sy.pse (hsa04726 ) Long-term depression (hsa04730 ) Regulation of actin cytoskeleton (hsa04810 ) Insulin sig.ling pathway (hsa04910 ) GnRH sig.ling pathway (hsa04912 ) Progesterone-mediated oocyte maturation (hsa04914 ) Estrogen sig.ling pathway (hsa04915 ) Melanogenesis (hsa04916 ) Prolactin sig.ling pathway (hsa04917 ) Thyroid hormone sig.ling pathway (hsa04919 ) Oxytocin sig.ling pathway (hsa04921 ) Relaxin sig.ling pathway (hsa04926 ) GnRH secretion (hsa04929 ) AGE-RAGE sig.ling pathway in diabetic complications (hsa04933 ) Growth hormone synthesis, secretion and action (hsa04935 ) Aldosterone-regulated sodium reabsorption (hsa04960 ) Alzheimer disease (hsa05010 ) Pathways of neurodegeneration - multiple diseases (hsa05022 ) Alcoholism (hsa05034 ) Hepatitis C (hsa05160 ) Hepatitis B (hsa05161 ) Human cytomegalovirus infection (hsa05163 ) Human papillomavirus infection (hsa05165 ) Human T-cell leukemia virus 1 infection (hsa05166 ) Kaposi sarcoma-associated herpesvirus infection (hsa05167 ) Human immunodeficiency virus 1 infection (hsa05170 ) Pathways in cancer (hsa05200 ) Viral carcinogenesis (hsa05203 ) Proteoglycans in cancer (hsa05205 ) MicroR.s in cancer (hsa05206 ) Chemical carcinogenesis - receptor activation (hsa05207 ) Chemical carcinogenesis - reactive oxygen species (hsa05208 ) Colorectal cancer (hsa05210 ) Re.l cell carcinoma (hsa05211 ) Pancreatic cancer (hsa05212 ) Endometrial cancer (hsa05213 ) Glioma (hsa05214 ) Prostate cancer (hsa05215 ) Thyroid cancer (hsa05216 ) Melanoma (hsa05218 ) Bladder cancer (hsa05219 ) Chronic myeloid leukemia (hsa05220 ) Acute myeloid leukemia (hsa05221 ) Non-small cell lung cancer (hsa05223 ) Breast cancer (hsa05224 ) Hepatocellular carcinoma (hsa05225 ) Gastric cancer (hsa05226 ) Central carbon metabolism in cancer (hsa05230 ) Choline metabolism in cancer (hsa05231 ) PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 ) Lipid and atherosclerosis (hsa05417 )
Reactome Pathway	Activation of RAS in B cells (R-HSA-1169092 ) Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants (R-HSA-1236382 ) SHC1 events in ERBB2 signaling (R-HSA-1250196 ) SHC1 events in ERBB4 signaling (R-HSA-1250347 ) Signaling by SCF-KIT (R-HSA-1433557 ) Signalling to RAS (R-HSA-167044 ) p38MAPK events (R-HSA-171007 ) GRB2 events in EGFR signaling (R-HSA-179812 ) SHC1 events in EGFR signaling (R-HSA-180336 ) Downstream signal transduction (R-HSA-186763 ) GRB2 events in ERBB2 signaling (R-HSA-1963640 ) Tie2 Signaling (R-HSA-210993 ) EGFR Transactivation by Gastrin (R-HSA-2179392 ) DAP12 signaling (R-HSA-2424491 ) SHC-related events triggered by IGF1R (R-HSA-2428933 ) FCERI mediated MAPK activation (R-HSA-2871796 ) NCAM signaling for neurite out-growth (R-HSA-375165 ) Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982 ) VEGFR2 mediated cell proliferation (R-HSA-5218921 ) CD209 (DC-SIGN) signaling (R-HSA-5621575 ) Constitutive Signaling by EGFRvIII (R-HSA-5637810 ) SHC-mediated cascade (R-HSA-5654688 ) FRS-mediated FGFR1 signaling (R-HSA-5654693 ) SHC-mediated cascade (R-HSA-5654699 ) FRS-mediated FGFR2 signaling (R-HSA-5654700 ) SHC-mediated cascade (R-HSA-5654704 ) FRS-mediated FGFR3 signaling (R-HSA-5654706 ) FRS-mediated FGFR4 signaling (R-HSA-5654712 ) SHC-mediated cascade (R-HSA-5654719 ) Signaling by FGFR2 in disease (R-HSA-5655253 ) Signaling by FGFR4 in disease (R-HSA-5655291 ) Signaling by FGFR1 in disease (R-HSA-5655302 ) Signaling by FGFR3 in disease (R-HSA-5655332 ) Regulation of RAS by GAPs (R-HSA-5658442 ) RAF activation (R-HSA-5673000 ) RAF/MAP kinase cascade (R-HSA-5673001 ) 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 ) RAS signaling downstream of NF1 loss-of-function variants (R-HSA-6802953 ) Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955 ) Insulin receptor signalling cascade (R-HSA-74751 ) PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases (R-HSA-8849471 ) MET activates RAS signaling (R-HSA-8851805 ) RUNX3 regulates p14-ARF (R-HSA-8951936 ) Activated NTRK2 signals through RAS (R-HSA-9026519 ) Erythropoietin activates RAS (R-HSA-9027284 ) Activated NTRK2 signals through FRS2 and FRS3 (R-HSA-9028731 ) Activated NTRK3 signals through RAS (R-HSA-9034864 ) FLT3 Signaling (R-HSA-9607240 ) Constitutive Signaling by Overexpressed ERBB2 (R-HSA-9634285 ) Estrogen-stimulated signaling through PRKCZ (R-HSA-9634635 ) RAS processing (R-HSA-9648002 ) Signaling downstream of RAS mutants (R-HSA-9649948 ) Signaling by RAF1 mutants (R-HSA-9656223 ) Signaling by ERBB2 KD Mutants (R-HSA-9664565 ) Signaling by ERBB2 ECD mutants (R-HSA-9665348 ) Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686 ) Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants (R-HSA-9670439 ) Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants (R-HSA-9673767 ) Signaling by PDGFRA extracellular domain mutants (R-HSA-9673770 ) Signaling by CSF3 (G-CSF) (R-HSA-9674555 ) Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350 ) Signaling by FLT3 fusion proteins (R-HSA-9703465 ) Signaling by FLT3 ITD and TKD mutants (R-HSA-9703648 ) Signaling by RAS GAP mutants (R-HSA-9753510 ) Signaling by RAS GTPase mutants (R-HSA-9753512 ) SOS-mediated signalling (R-HSA-112412 )

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Cardiofaciocutaneous syndrome 1	DISV4HQA	Definitive	Autosomal dominant	[1]
Cardiofaciocutaneous syndrome 2	DISJMMVB	Definitive	Autosomal dominant	[2]
Noonan syndrome	DIS7Q7DN	Definitive	Autosomal dominant	[3]
Noonan syndrome 3	DIS4MLJP	Definitive	Autosomal dominant	[4]
Cardiofaciocutaneous syndrome	DISZJKSC	Strong	Autosomal dominant	[3]
Linear nevus sebaceous syndrome	DIS6VQ2J	Strong	Autosomal dominant	[5]
Costello syndrome	DISXVJH3	Disputed	Autosomal dominant	[3]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 15 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	GTPase KRas (KRAS) increases the response to substance of Methotrexate.	[37]
Sulindac	DM2QHZU	Approved	GTPase KRas (KRAS) affects the response to substance of Sulindac.	[38]
Gefitinib	DM15F0X	Approved	GTPase KRas (KRAS) decreases the response to substance of Gefitinib.	[39]
Crizotinib	DM4F29C	Approved	GTPase KRas (KRAS) decreases the response to substance of Crizotinib.	[40]
Lapatinib	DM3BH1Y	Approved	GTPase KRas (KRAS) decreases the response to substance of Lapatinib.	[39]
Vemurafenib	DM62UG5	Approved	GTPase KRas (KRAS) affects the response to substance of Vemurafenib.	[41]
Pemetrexed	DMMX2E6	Approved	GTPase KRas (KRAS) increases the response to substance of Pemetrexed.	[37]
Dabrafenib	DMX6OE3	Approved	GTPase KRas (KRAS) affects the response to substance of Dabrafenib.	[41]
Sotorasib	DMLSV74	Approved	GTPase KRas (KRAS) increases the response to substance of Sotorasib.	[42]
Trimetrexate	DMDEA85	Approved	GTPase KRas (KRAS) increases the response to substance of Trimetrexate.	[37]
Afimoxifene	DMFORDT	Phase 2	GTPase KRas (KRAS) affects the response to substance of Afimoxifene.	[43]
GDC0941	DM1YAK6	Phase 2	GTPase KRas (KRAS) increases the response to substance of GDC0941.	[44]
PF-04691502	DMS610L	Phase 2	GTPase KRas (KRAS) affects the response to substance of PF-04691502.	[45]
(+)-JQ1	DM1CZSJ	Phase 1	GTPase KRas (KRAS) increases the response to substance of (+)-JQ1.	[46]
AZ-628	DMEWQHP	Investigative	GTPase KRas (KRAS) increases the response to substance of AZ-628.	[47]
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⏷ Show the Full List of 15 Drug(s)

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Guanosine-5'-Triphosphate	DMV2OJX	Investigative	GTPase KRas (KRAS) increases the hydrolysis of Guanosine-5'-Triphosphate.	[36]
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28 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 GTPase KRas (KRAS).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GTPase KRas (KRAS).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of GTPase KRas (KRAS).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of GTPase KRas (KRAS).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GTPase KRas (KRAS).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic increases the mutagenesis of GTPase KRas (KRAS).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of GTPase KRas (KRAS).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of GTPase KRas (KRAS).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of GTPase KRas (KRAS).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of GTPase KRas (KRAS).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of GTPase KRas (KRAS).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of GTPase KRas (KRAS).	[17]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of GTPase KRas (KRAS).	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of GTPase KRas (KRAS).	[19]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of GTPase KRas (KRAS).	[13]
Sevoflurane	DMC9O43	Approved	Sevoflurane decreases the expression of GTPase KRas (KRAS).	[22]
Tiazofurin	DM5JWV9	Approved	Tiazofurin decreases the expression of GTPase KRas (KRAS).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of GTPase KRas (KRAS).	[24]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of GTPase KRas (KRAS).	[25]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of GTPase KRas (KRAS).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of GTPase KRas (KRAS).	[27]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of GTPase KRas (KRAS).	[29]
MANUMYCIN A	DM1SWOY	Terminated	MANUMYCIN A decreases the activity of GTPase KRas (KRAS).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the mutagenesis of GTPase KRas (KRAS).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of GTPase KRas (KRAS).	[32]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of GTPase KRas (KRAS).	[33]
acrolein	DMAMCSR	Investigative	acrolein decreases the expression of GTPase KRas (KRAS).	[34]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of GTPase KRas (KRAS).	[35]
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⏷ Show the Full List of 28 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Simvastatin decreases the prenylation of GTPase KRas (KRAS).	[20]
Lovastatin	DM9OZWQ	Approved	Lovastatin decreases the prenylation of GTPase KRas (KRAS).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of GTPase KRas (KRAS).	[28]
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1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Guanosine-5'-Diphosphate	DM0MUKQ	Investigative	Guanosine-5'-Diphosphate affects the binding of GTPase KRas (KRAS).	[36]
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