Target Information

Target General Information

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Target ID

T48598 (Former ID: TTDNC00549)

Target Name

GTPase KRas (KRAS)

Synonyms

c-Ki-ras; c-K-ras; RASK2; Ki-Ras; KRAS2; K-Ras 2

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Gene Name

KRAS

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

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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BioChemical Class

Small GTPase

UniProt ID

RASK_HUMAN

Sequence

MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
QEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDL
PSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGC
VKIKKCIIM

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3D Structure

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PDB

HIT2.0 ID

T92ZDN

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

AZD4785

Drug Info

Phase 1

Solid tumour/cancer

[1]

BI 1701963

Drug Info

Phase 1

Solid tumour/cancer

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 2 Inhibitor drugs

AZD4785

Drug Info

[1]

BI 1701963

Drug Info

[3]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Promazine

Ligand Info

Structure Description

The haddock model of GDP KRas in complex with promazine using chemical shift perturbations and intermolecular NOEs

PDB:7LGI

Method

Solution NMR

Resolution

N.A.

Mutation

[4]

PDB Sequence

MTEYKLVVVG

¹⁰

AGGVGKSALT

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

REIRKHKEK

Residue

Distance (Å)

LYS5

2.253

LEU6

2.603

VAL7

2.372

GLU37

2.574

SER39

2.501

ARG41

2.076

ASP54

2.505

ILE55

3.890

LEU56

2.415

THR58

4.786

Residue

Distance (Å)

MET67

2.463

GLN70

4.759

TYR71

2.173

MET72

4.599

ARG73

4.957

THR74

2.686

GLY75

2.132

GLU76

3.912

PHE78

4.673

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

[5]

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

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). 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). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

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).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
ADP-ribosylation factor-like protein 4A (ARL4A)	PF00025	23.729 (28/118)	1.89E-06
ADP-ribosylation factor-like protein 8B (ARL8B)	PF00025	26.923 (35/130)	4.53E-06
ADP-ribosylation factor-like protein 4C (ARL4C)	PF00025	23.741 (33/139)	4.12E-05
ADP-ribosylation factor-like protein 4D (ARL4D)	PF00025	24.576 (29/118)	9.51E-05
ADP-ribosylation factor-like protein 8A (ARL8A)	PF00025	23.846 (31/130)	1.63E-04
ADP-ribosylation factor-like protein 14 (ARL14)	PF00025	22.628 (31/137)	1.00E-03
ADP-ribosylation factor 4 (ARF4)	PF00025	21.667 (26/120)	3.00E-03
Ras-related GTP-binding protein A (RRAGA)	PF04670	22.308 (29/130)	3.00E-03
Click to Show/Hide the Information of Human Similarity Proteins


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

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
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	68	Degree centrality	7.31E-03	Betweenness centrality	2.23E-03
Closeness centrality	2.60E-01	Radiality	1.45E+01	Clustering coefficient	1.67E-01
Neighborhood connectivity	3.95E+01	Topological coefficient	4.15E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 76 KEGG Pathways	+
1	EGFR tyrosine kinase inhibitor resistance
2	Endocrine resistance
3	MAPK signaling pathway
4	ErbB signaling pathway
5	Ras signaling pathway
6	Rap1 signaling pathway
7	Chemokine signaling pathway
8	FoxO signaling pathway
9	Sphingolipid signaling pathway
10	Phospholipase D signaling pathway
11	Mitophagy - animal
12	Autophagy - animal
13	mTOR signaling pathway
14	PI3K-Akt signaling pathway
15	Apoptosis
16	Longevity regulating pathway
17	Longevity regulating pathway - multiple species
18	Cellular senescence
19	Axon guidance
20	VEGF signaling pathway
21	Apelin signaling pathway
22	Gap junction
23	Signaling pathways regulating pluripotency of stem cells
24	C-type lectin receptor signaling pathway
25	Natural killer cell mediated cytotoxicity
26	T cell receptor signaling pathway
27	B cell receptor signaling pathway
28	Fc epsilon RI signaling pathway
29	Thermogenesis
30	Long-term potentiation
31	Neurotrophin signaling pathway
32	Cholinergic synapse
33	Serotonergic synapse
34	Long-term depression
35	Regulation of actin cytoskeleton
36	Insulin signaling pathway
37	GnRH signaling pathway
38	Progesterone-mediated oocyte maturation
39	Estrogen signaling pathway
40	Melanogenesis
41	Prolactin signaling pathway
42	Thyroid hormone signaling pathway
43	Oxytocin signaling pathway
44	Relaxin signaling pathway
45	AGE-RAGE signaling pathway in diabetic complications
46	Aldosterone-regulated sodium reabsorption
47	Alcoholism
48	Hepatitis C
49	Hepatitis B
50	Human cytomegalovirus infection
51	Human papillomavirus infection
52	Human T-cell leukemia virus 1 infection
53	Kaposi sarcoma-associated herpesvirus infection
54	Human immunodeficiency virus 1 infection
55	Pathways in cancer
56	Viral carcinogenesis
57	Proteoglycans in cancer
58	MicroRNAs in cancer
59	Colorectal cancer
60	Renal cell carcinoma
61	Pancreatic cancer
62	Endometrial cancer
63	Glioma
64	Prostate cancer
65	Thyroid cancer
66	Melanoma
67	Bladder cancer
68	Chronic myeloid leukemia
69	Acute myeloid leukemia
70	Non-small cell lung cancer
71	Breast cancer
72	Hepatocellular carcinoma
73	Gastric cancer
74	Central carbon metabolism in cancer
75	Choline metabolism in cancer
76	PD-L1 expression and PD-1 checkpoint pathway in cancer

References

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REF 1

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 2

ClinicalTrials.gov (NCT04835714) A Study to Find a Safe and Effective Dose of BI 1701963 Alone and in Combination With BI 3011441 in Patients With Advanced Cancer and a Certain Mutation (KRAS). U.S. National Institutes of Health.

REF 3

Clinical pipeline report, company report or official report of Boehringer Ingelheim.

REF 4

Antipsychotic phenothiazine drugs bind to KRAS in vitro. J Biomol NMR. 2021 Jul;75(6-7):233-244.

REF 5

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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