Target Information

Target General Information

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Target ID

T59480

Target Name

KRAS G12C mutant (KRAS G12C)

Gene Name

KRAS

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Non-small-cell lung cancer [ICD-11: 2C25]

UniProt ID

RASK_HUMAN

Sequence

MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
QEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDL
PSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGC
VKIKKCIIM

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Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Adagrasib

Drug Info

Approved

Non-small-cell lung cancer

[2]

Sotorasib

Drug Info

Approved

Non-small-cell lung cancer

[3]

Clinical Trial Drug(s)

[+] 4 Clinical Trial Drugs

JDQ443

Drug Info

Phase 3

Non-small-cell lung cancer

[4]

LY3499446

Drug Info

Phase 1/2

Solid tumour/cancer

[5]

JNJ-74699157

Drug Info

Phase 1

Solid tumour/cancer

[6]

RG6330

Drug Info

Phase 1

Solid tumour/cancer

[7]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 6 Inhibitor drugs

Adagrasib

Drug Info

[8]

Sotorasib

Drug Info

[1]

JDQ443

Drug Info

[9]

LY3499446

Drug Info

[10]

JNJ-74699157

Drug Info

[10]

RG6330

Drug Info

[7]

Drug Binding Sites of Target

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Ligand Name: Guanosine-5'-Diphosphate

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF KRAS-G12C IN COMPLEX WITH COMPOUND 23 (BI-0474)

PDB:8AFB

Method

X-ray diffraction

Resolution

1.12 Å

Mutation

Yes

[11]

PDB Sequence

TEYKLVVVGA

¹¹

CGVGKSALTI

²¹

QLIQNHFVDE

³¹

YDPTIEDSYR

⁴¹

KQVVIDGETC

⁵¹

LLDILDTAGQ

⁶¹

EEYSAMRDQY

⁷¹

MRTGEGFLCV

⁸¹

FAINNTKSFE

⁹¹

DIHHYREQIK

¹⁰¹

RVKDSEDVPM

¹¹¹

VLVGNKSDLP

¹²¹

SRTVDTKQAQ

¹³¹

DLARSYGIPF

¹⁴¹

IETSAKTRQG

¹⁵¹

VDDAFYTLVR

¹⁶¹

EIRK

Residue

Distance (Å)

ALA11

3.830

CYS12

3.663

GLY13

2.764

VAL14

3.355

GLY15

3.006

LYS16

2.782

SER17

2.931

ALA18

2.887

PHE28

4.030

VAL29

4.969

ASP30

2.686

GLU31

4.674

Residue

Distance (Å)

TYR32

3.701

PRO34

4.645

ASP57

4.529

ASN116

3.221

LYS117

3.039

SER118

4.808

ASP119

2.796

LEU120

3.524

THR144

4.801

SER145

3.456

ALA146

2.813

LYS147

3.409

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: K-Ras(G12C) inhibitor 6

Ligand Info

Structure Description

Crystal Structure of small molecule disulfide 6 bound to K-Ras G12C

PDB:4LUC

Method

X-ray diffraction

Resolution

1.29 Å

Mutation

Yes

[12]

PDB Sequence

MTEYKLVVVG

¹⁰

ACGVGKSALT

²⁰

IQLIQNHFVD

³⁰

EYDPTIEDSY

⁴⁰

RKQVVIDGET

⁵⁰

SLLDILDTAG

⁶⁰

QEEYSAMRDQ

⁷⁰

YMRTGEGFLL

⁸⁰

VFAINNTKSF

⁹⁰

EDIHHYREQI

¹⁰⁰

KRVKDSEDVP

¹¹⁰

MVLVGNKSDL

¹²⁰

PSRTVDTKQA

¹³⁰

QDLARSYGIP

¹⁴⁰

FIETSAKTRQ

¹⁵⁰

GVDDAFYTLV

¹⁶⁰

REIRKHKE

Residue

Distance (Å)

VAL7

2.861

VAL9

2.719

GLY10

2.737

ALA11

2.567

CYS12

2.035

GLY13

3.393

LYS16

3.981

PRO34

3.242

THR35

4.735

LEU56

4.241

THR58

2.390

ALA59

4.071

Residue

Distance (Å)

GLY60

1.858

GLN61

2.567

GLU62

2.528

GLU63

3.946

ARG68

2.698

TYR71

3.057

MET72

2.259

PHE78

3.363

TYR96

2.594

ARG97

4.825

GLN99

2.817

ILE100

2.611

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 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 Similarity Proteins Human Pathway Affiliation

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 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 Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
ADP-ribosylation factor-like protein 4A (ARL4A)	PF00025	23.729 (28/118)	3.33E-06
ADP-ribosylation factor-like protein 8B (ARL8B)	PF00025	26.923 (35/130)	4.90E-06
ADP-ribosylation factor-like protein 4C (ARL4C)	PF00025	23.741 (33/139)	7.69E-05
ADP-ribosylation factor-like protein 4D (ARL4D)	PF00025	24.576 (29/118)	9.24E-05
ADP-ribosylation factor-like protein 8A (ARL8A)	PF00025	23.846 (31/130)	1.63E-04
ADP-ribosylation factor-like protein 14 (ARL14)	PF00025	25.287 (22/87)	2.00E-03
Intraflagellar transport protein 22 homolog (IFT22)	PF08477	26.136 (23/88)	4.00E-03
ADP-ribosylation factor 4 (ARF4)	PF00025	21.667 (26/120)	4.00E-03
Ras-related GTP-binding protein A (RRAGA)	PF04670	22.308 (29/130)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins

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

References

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REF 1

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

REF 2

FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 216340.

REF 3

FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 214665.

REF 4

ClinicalTrials.gov (NCT05132075) A Randomized, Controlled, Open Label, Phase III Study Evaluating the Efficacy and Safety of JDQ443 Versus Docetaxel in Previously Treated Subjects With Locally Advanced or Metastatic KRAS G12C Mutant Non-small Cell Lung Cancer. U.S.National Institutes of Health.

REF 5

ClinicalTrials.gov (NCT04165031) A Study of LY3499446 in Participants With Advanced Solid Tumors With KRAS G12C Mutation. U.S. National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT04006301) First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation. U.S. National Institutes of Health.

REF 7

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

REF 8

Clinical pipeline report, company report or official report of Mirati Therapeutics.

REF 9

Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C. Cancer Discov. 2022 Jun 2;12(6):1500-1517.

REF 10

KRAS: From undruggable to a druggable Cancer Target. Cancer Treat Rev. 2020 Sep;89:102070.

REF 11

Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS(G12C) Inhibitor. J Med Chem. 2022 Nov 10;65(21):14614-14629.

REF 12

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013 Nov 28;503(7477):548-51.

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