Target Information

Target General Information

Target ID

T03046 (Former ID: TTDI01322)

Target Name

Mutated KRAS (mKRAS)

Synonyms

c-Ki-ras (mutated); c-K-ras (mutated); RASK2 (mutated); Ki-Ras (mutated); KRAS2 (mutated); K-Ras 2 (mutated); GTPase KRas (mutated)

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Gene Name

KRAS

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Pancreatic cancer [ICD-11: 2C10]

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.

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UniProt ID

RASK_HUMAN

Sequence

MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
QEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDL
PSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGC
VKIKKCIIM

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Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

GI-4000 + gemcitabine

Drug Info

Phase 2

Pancreatic cancer

[1]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 1 Modulator drugs

GI-4000 + gemcitabine

Drug Info

[1]

Drug Binding Sites of Target

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Ligand Name: Benzimidazole

Ligand Info

Structure Description

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

PDB:4DSU

Method

X-ray diffraction

Resolution

1.70 Å

Mutation

Yes

[2]

PDB Sequence

STEYKLVVVG

¹⁰

ADGVGKSALT

²⁰

IQLIQNHFVD

³⁰

EYDPTIEDSY

⁴⁰

RKQVVIDGET

⁵⁰

CLLDILDTAG

⁶⁰

QSAMRDQYMR

⁷³

TGEGFLCVFA

⁸³

INNTKSFEDI

⁹³

HHYREQIKRV

¹⁰³

KDSEDVPMVL

¹¹³

VGNKCDLPSR

¹²³

TVDTKQAQDL

¹³³

ARSYGIPFIE

¹⁴³

TSAKTRQGVD

¹⁵³

DAFYTLVREI

¹⁶³

RKHKEKMSKD

¹⁷³

GKKKKKK

Residue

Distance (Å)

LYS5

3.502

LEU6

3.631

VAL7

3.645

SER39

3.730

ARG41

4.213

ASP54

2.765

Residue

Distance (Å)

ILE55

4.247

LEU56

3.720

TYR71

3.805

THR74

3.791

GLY75

4.306

Ligand Name: 5'-Guanosine-Diphosphate-Monothiophosphate

Ligand Info

Structure Description

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

PDB:4DSO

Method

X-ray diffraction

Resolution

1.85 Å

Mutation

Yes

[2]

PDB Sequence

STEYKLVVVG

¹⁰

ADGVGKSALT

²⁰

IQLIQNHFVD

³⁰

EYDPTIEDSY

⁴⁰

RKQVVIDGET

⁵⁰

CLLDILDTAG

⁶⁰

QEEYSAMRDQ

⁷⁰

YMRTGEGFLC

⁸⁰

VFAINNTKSF

⁹⁰

EDIHHYREQI

¹⁰⁰

KRVKDSEDVP

¹¹⁰

MVLVGNKCDL

¹²⁰

PSRTVDTKQA

¹³⁰

QDLARSYGIP

¹⁴⁰

FIETSAKTRQ

¹⁵⁰

GVDDAFYTLV

¹⁶⁰

REIRKHKEKM

¹⁷⁰

SKDGKKKKKK

¹⁸⁰

Residue

Distance (Å)

GLY10

4.858

ALA11

3.831

ASP12

3.622

GLY13

2.873

VAL14

3.297

GLY15

2.953

LYS16

2.639

SER17

2.883

ALA18

2.837

PHE28

3.282

VAL29

2.631

ASP30

2.972

GLU31

3.444

TYR32

2.508

ASP33

4.301

PRO34

3.882

Residue

Distance (Å)

THR35

2.842

ASP57

4.600

THR58

3.896

ALA59

3.759

GLY60

2.703

GLN61

4.034

ASN116

3.211

LYS117

2.996

CYS118

4.981

ASP119

2.666

LEU120

3.257

THR144

4.834

SER145

3.495

ALA146

2.866

LYS147

3.382

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Different Human System Profiles of Target	Top
Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Pathway Affiliation

Different Human System Profiles of Target

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Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Pathway Affiliation

KEGG Pathway	Pathway ID	Affiliated Target
MAPK signaling pathway	hsa04010	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
ErbB signaling pathway	hsa04012	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Ras signaling pathway	hsa04014	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Rap1 signaling pathway	hsa04015	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Chemokine signaling pathway	hsa04062	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
FoxO signaling pathway	hsa04068	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Sphingolipid signaling pathway	hsa04071	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Phospholipase D signaling pathway	hsa04072	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Mitophagy - animal	hsa04137	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Autophagy - animal	hsa04140	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
mTOR signaling pathway	hsa04150	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
PI3K-Akt signaling pathway	hsa04151	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Apoptosis	hsa04210	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Longevity regulating pathway	hsa04211	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy
Longevity regulating pathway - multiple species	hsa04213	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy
Cellular senescence	hsa04218	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Axon guidance	hsa04360	Affiliated Target
Class: Organismal Systems => Development and regeneration	Pathway Hierarchy
VEGF signaling pathway	hsa04370	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Apelin signaling pathway	hsa04371	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Gap junction	hsa04540	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
Signaling pathways regulating pluripotency of stem cells	hsa04550	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
C-type lectin receptor signaling pathway	hsa04625	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Natural killer cell mediated cytotoxicity	hsa04650	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
T cell receptor signaling pathway	hsa04660	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
B cell receptor signaling pathway	hsa04662	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Fc epsilon RI signaling pathway	hsa04664	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Thermogenesis	hsa04714	Affiliated Target
Class: Organismal Systems => Environmental adaptation	Pathway Hierarchy
Long-term potentiation	hsa04720	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Neurotrophin signaling pathway	hsa04722	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Cholinergic synapse	hsa04725	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Serotonergic synapse	hsa04726	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Long-term depression	hsa04730	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Regulation of actin cytoskeleton	hsa04810	Affiliated Target
Class: Cellular Processes => Cell motility	Pathway Hierarchy
Insulin signaling pathway	hsa04910	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
GnRH signaling pathway	hsa04912	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Progesterone-mediated oocyte maturation	hsa04914	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Estrogen signaling pathway	hsa04915	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Melanogenesis	hsa04916	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Prolactin signaling pathway	hsa04917	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Thyroid hormone signaling pathway	hsa04919	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Oxytocin signaling pathway	hsa04921	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Relaxin signaling pathway	hsa04926	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
GnRH secretion	hsa04929	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Growth hormone synthesis, secretion and action	hsa04935	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Aldosterone-regulated sodium reabsorption	hsa04960	Affiliated Target
Class: Organismal Systems => Excretory system	Pathway Hierarchy
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References

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REF 1

Clinical pipeline report, company report or official report of GlobeImmune.

REF 2

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5299-304.

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