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Avutometinib

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Also known as CH-5126766CH5126766CKI-27R-7304Rg-7304Ro 5126766Ro-5126766VS-6766RO5126766 (CH5126766)

Summary

Avutometinib (CHEMBL3264002) is a phase-3 clinical-stage small-molecule EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor targeting MAP2K1 and RAF1; indicated across 13 conditions including ovarian cancer and non-small cell lung carcinoma.

At a glance

  • Status: Max clinical phase 3 (not approved)
  • Modality: Small molecule
  • Targets: 2 (MAP2K1, RAF1)
  • Indications: 13 conditions
  • Clinical trials: 25
  • Chemistry: 471.5 Da · C21H18FN5O5S

Identifiers

Drug identity and classification

FieldValue
ChEMBL IDCHEMBL3264002
NameAvutometinib
TypeSmall molecule
Max phase3
FDA approvedno
PubChem CID16719221
ChEBICHEBI:78825
Molecular formulaC21H18FN5O5S
Molecular weight471.5
InChIKeyLMMJFBMMJUMSJS-UHFFFAOYSA-N

SMILES: CC1=C(C(=O)OC2=C1C=CC(=C2)OC3=NC=CC=N3)CC4=C(C(=NC=C4)NS(=O)(=O)NC)F

IUPAC name: 3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridinyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one

ChEBI definition: A member of the class of coumarins that is 4-methyl-7-[(pyrimidin-2-yl)oxy]coumarin carrying an additional [2-[(methylaminosulfonyl)amino]-3-fluoropyridin-4-yl]methyl substituent at position 3.

Pharmacological roles (ChEBI): EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor, antineoplastic agent.

Also known as: Avutometinib, CH-5126766, CH5126766, CKI-27, R-7304, Rg-7304, Ro 5126766, Ro-5126766, VS-6766, AVUTOMETINIB, RO5126766 (CH5126766)

Parent form; salt/anhydrous children: CHEMBL3264004

Patent coverage: 820 distinct patent families (2,208 SureChEMBL compound mentions), from 4 matched compound structure(s). One matched structure accounts for 1,636 (74%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

GeneTargetActionpAffinityCancer dependencyUniProt
MAP2K1mitogen-activated protein kinase kinase 1Inhibition6.84.7%Q02750
RAF1Raf-1 proto-oncogene, serine/threonine kinaseInhibition7.25P04049

Broader ChEMBL bioactivity targets: 7 (assay-derived). Sample: RAF proto-oncogene serine/threonine-protein kinase, Dual specificity mitogen-activated protein kinase kinase; MEK1/2, Dual specificity mitogen-activated protein kinase kinase 2, Cytochrome P450 2C9, Dual specificity mitogen-activated protein kinase kinase 1, Dual specificity mitogen-activated protein kinase kinase 5, Serine/threonine-protein kinase B-raf.

Bioactivity

ChEMBL activities: 12 potent at pChembl ≥ 5 of 14 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

TargetpChemblTypeValueUnitActivity ID
BRAF8.15Kd7nMCHEMBL_ACT_17885864
BRAF8.09IC508.2nMCHEMBL_ACT_24691458
BRAF7.72IC5019nMCHEMBL_ACT_24691457
MAP2K17.52Kd30nMCHEMBL_ACT_17910326
MAP2K27.43Kd37nMCHEMBL_ACT_17910652
RAF17.25IC5056nMCHEMBL_ACT_14653712
RAF17.25IC5056nMCHEMBL_ACT_24691456
MAP2K16.8IC50160nMCHEMBL_ACT_14653725
MAP2K16.8IC50160nMCHEMBL_ACT_24999394
MAP2K16.8IC50160nMCHEMBL_ACT_25892743
MAP2K26.8IC50160nMCHEMBL_ACT_29048810
MAP2K55.7Kd1996nMCHEMBL_ACT_17911212

Target pathways

Aggregated over 2 target gene(s): MAP2K1, RAF1.

Top Reactome pathways

68 total, by targets touching each:

PathwayTargetsGenes
RAF activation2MAP2K1, RAF1
MAP2K and MAPK activation2MAP2K1, RAF1
Negative feedback regulation of MAPK pathway2MAP2K1, RAF1
Negative regulation of MAPK pathway2MAP2K1, RAF1
Signaling by moderate kinase activity BRAF mutants2MAP2K1, RAF1
Signaling by high-kinase activity BRAF mutants2MAP2K1, RAF1
Signaling by BRAF and RAF1 fusions2MAP2K1, RAF1
Paradoxical activation of RAF signaling by kinase inactive BRAF2MAP2K1, RAF1
Signaling downstream of RAS mutants2MAP2K1, RAF1
Signaling by RAF1 mutants2MAP2K1, RAF1
MAPK3 (ERK1) activation1MAP2K1
RAF-independent MAPK1/3 activation1MAP2K1
Developmental Biology1MAP2K1
Cytokine Signaling in Immune system1MAP2K1
Signal Transduction1MAP2K1
Disease1MAP2K1
Toll Like Receptor 4 (TLR4) Cascade1MAP2K1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane1MAP2K1
MyD88-independent TLR4 cascade1MAP2K1
Signaling by NTRKs1MAP2K1
Toll Like Receptor 9 (TLR9) Cascade1MAP2K1
Toll Like Receptor 10 (TLR10) Cascade1MAP2K1
Toll Like Receptor 3 (TLR3) Cascade1MAP2K1
Toll Like Receptor 5 (TLR5) Cascade1MAP2K1
Toll Like Receptor TLR1:TLR2 Cascade1MAP2K1
Toll Like Receptor 7/8 (TLR7/8) Cascade1MAP2K1
Toll Like Receptor TLR6:TLR2 Cascade1MAP2K1
Innate Immune System1MAP2K1
Immune System1MAP2K1
Toll-like Receptor Cascades1MAP2K1
Prolonged ERK activation events1MAP2K1
Frs2-mediated activation1MAP2K1
Toll Like Receptor 2 (TLR2) Cascade1MAP2K1
Signaling by NTRK1 (TRKA)1MAP2K1
Signalling to ERKs1MAP2K1
Stimuli-sensing channels1RAF1
L1CAM interactions1MAP2K1
Rap1 signalling1RAF1
Axon guidance1MAP2K1
GP1b-IX-V activation signalling1RAF1
Signal transduction by L11MAP2K1
Interleukin-1 family signaling1MAP2K1
Interleukin-17 signaling1MAP2K1
Signaling by Interleukins1MAP2K1
MAP kinase activation1MAP2K1
Uptake and function of anthrax toxins1MAP2K1
Uptake and actions of bacterial toxins1MAP2K1
CD209 (DC-SIGN) signaling1RAF1
Diseases of signal transduction by growth factor receptors and second messengers1MAP2K1
Infectious disease1MAP2K1

Dominant GO biological processes

GO termTargets
MAPK cascade2
signal transduction2
negative regulation of cell population proliferation2
Schwann cell development2
thyroid gland development2
ERBB2-ERBB3 signaling pathway2
myelination2
type B pancreatic cell proliferation2
insulin-like growth factor receptor signaling pathway2
thymus development2
face development2
protein phosphorylation2
positive regulation of MAPK cascade2
regulation of vascular associated smooth muscle contraction1
chemotaxis1

Indications & clinical

Indications

12 diseases in clinical trials (phase 1–3, investigational — not approved indications). Highest ChEMBL trial phase per disease; a non-cancer approved use is occasionally logged at phase 3 here.

Disease (in trials)PhaseMONDOEFO
ovarian cancer3MONDO:0008170MONDO:0008170
non-small cell lung carcinoma2MONDO:0005233EFO:0003060
female reproductive system neoplasm2MONDO:0021148MONDO:0021148
colorectal adenocarcinoma2MONDO:0005008EFO:0000365
thyroid gland carcinoma2MONDO:0015075EFO:0002892
uveal melanoma2MONDO:0006486EFO:1000616
colorectal neoplasm2MONDO:0005335MONDO:0005575
endometrioid adenocarcinoma1MONDO:0005026EFO:0000466
neoplasm1MONDO:0005070EFO:0000616
plasma cell myeloma1MONDO:0009693EFO:0001378
exocrine pancreatic carcinoma1MONDO:0005192EFO:0002618
melanoma1MONDO:0005105EFO:0000756

Clinical trials

Total trials: 25.

Phase distribution

PhaseTrials
PHASE211
PHASE1/PHASE27
PHASE15
PHASE31
EARLY_PHASE11

Top trials by phase / activity

NCTPhaseStatusTitle
NCT06072781PHASE3RECRUITINGA Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer
NCT04625270PHASE2ACTIVE_NOT_RECRUITINGA Study of Avutometinib (VS-6766) v. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation
NCT05074810PHASE1/PHASE2ACTIVE_NOT_RECRUITINGPhase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients
NCT05375994PHASE1/PHASE2ACTIVE_NOT_RECRUITINGStudy of Avutometinib (VS-6766) + Adagrasib in KRAS G12C NSCLC Patients
NCT05512208PHASE2RECRUITINGA Phase 2 Study of Avutometinib (VS-6766) Plus Defactinib
NCT05608252PHASE1/PHASE2RECRUITINGVS-6766+Abema+Fulv in Met HR+/HER- BC
NCT05669482PHASE1/PHASE2ACTIVE_NOT_RECRUITINGStudy of Avutometinib (VS-6766) +Defactinib With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer
NCT05787561PHASE2RECRUITINGA Study of Avutometinib (VS-6766) and Defactinib in People With Mesonephric Gynecologic Cancer
NCT06007924PHASE2RECRUITINGA Study of Avutometinib and Defactinib in People With Thyroid Cancer
NCT06194929PHASE1/PHASE2RECRUITINGDefactinib and Avutometinib, With or Without Encorafenib, for the Treatment of Patients With Brain Metastases From Cutaneous Melanoma
NCT06369259PHASE2RECRUITINGOpen-label Phase 2 Study of Avutometinib (RAF/MEK Clamp) in Combination With Defactinib (FAK Inhibitor) and Cetuximab in Patients With Unresectable, Anti-EGFR-Refractory Advanced Colorectal Cancer
NCT06394804PHASE2RECRUITINGA Study of Avutometinib, Defactinib, and Letrozole in People With Low-Grade Serous Ovarian Cancer
NCT06487221PHASE2RECRUITINGAvutometinib and Defactinib in Diffuse Gastric Cancer
NCT06495125PHASE2RECRUITINGDefactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer
NCT06630260PHASE1/PHASE2RECRUITING5G-RUBY: Avutometinib and Defactinib in Malignant Brain Tumours
NCT06682572PHASE2ACTIVE_NOT_RECRUITINGA Study of Avutometinib + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer in Japanese Patients
NCT07126158PHASE2RECRUITINGStereotactic Body Radiotherapy Plus FAK and RAF/MEK Inhibition in Advanced Pancreatic Adenocarcinoma
NCT04620330PHASE2COMPLETEDA Study of Avutometinib (VS-6766) + Defactinib in Recurrent KRAS G12V, Other KRAS and BRAF Non-Small Cell Lung Cancer
NCT05200442PHASE1/PHASE2SUSPENDEDA Study of VS-6766 and Cetuximab in Patients With Advanced Colorectal Cancer
NCT03875820PHASE1ACTIVE_NOT_RECRUITINGPhase I Trial of Defactinib and VS-6766.
NCT06104488PHASE1RECRUITINGA Study of Avutometinib for People With Solid Tumor Cancers
NCT07318324PHASE1NOT_YET_RECRUITINGPhase Ib Study of Avutometinib, Defactinib, and Everolimus in RAS Pathway Mutant Endometrial Cancer
NCT02407509PHASE1COMPLETEDPhase I Trial of VS-6766 Alone and in Combination With Everolimus
NCT05187169PHASE1COMPLETEDFood Effect of VS-6766 in Healthy Adult Subjects
NCT05798507EARLY_PHASE1ACTIVE_NOT_RECRUITINGIdentification of Treatment Concentrations of Defactinib or VS-6766 for the Treatment of Patients With Glioblastoma

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

64 molecules share ≥1 primary target. Top 64 by shared-target count:

MoleculeSourceStatusShared targets
PazopanibChEMBL + PubChemPhase 4 (approved)MAP2K1, RAF1
REGORAFENIBChEMBL + PubChemPhase 4 (approved)MAP2K1, RAF1
SELUMETINIBChEMBL + PubChemPhase 4 (approved)MAP2K1, RAF1
DASATINIBChEMBLPhase 4 (approved)MAP2K1, RAF1
SORAFENIBChEMBLPhase 4 (approved)MAP2K1, RAF1
VEMURAFENIBChEMBLPhase 4 (approved)MAP2K1, RAF1
CEP-32496ChEMBLPhase 2MAP2K1, RAF1
CI-1040ChEMBLPhase 2MAP2K1, RAF1
FORETINIBChEMBLPhase 2MAP2K1, RAF1
R-406ChEMBLPhase 2MAP2K1, RAF1
TOLONIUM CHLORIDEChEMBLPhase 2MAP2K1, RAF1
AfatinibPubChemApprovedMAP2K1, RAF1
CrizotinibPubChemApprovedMAP2K1, RAF1
GefitinibPubChemApprovedMAP2K1, RAF1
IdelalisibPubChemApprovedMAP2K1, RAF1
BINIMETINIBChEMBL + PubChemPhase 4 (approved)MAP2K1
TRAMETINIBChEMBL + PubChemPhase 4 (approved)MAP2K1
AXITINIBChEMBLPhase 4 (approved)MAP2K1
BOSUTINIBChEMBLPhase 4 (approved)MAP2K1
COBIMETINIBChEMBLPhase 4 (approved)MAP2K1
DABRAFENIBChEMBLPhase 4 (approved)RAF1
ERLOTINIBChEMBLPhase 4 (approved)RAF1
FEDRATINIBChEMBLPhase 4 (approved)MAP2K1
GILTERITINIBChEMBLPhase 4 (approved)MAP2K1
IMATINIBChEMBLPhase 4 (approved)RAF1
NERATINIBChEMBLPhase 4 (approved)MAP2K1
NILOTINIBChEMBLPhase 4 (approved)RAF1
NINTEDANIBChEMBLPhase 4 (approved)MAP2K1
RUXOLITINIBChEMBLPhase 4 (approved)MAP2K1
SUNITINIBChEMBLPhase 4 (approved)MAP2K1
TOFACITINIBChEMBLPhase 4 (approved)MAP2K1
TOVORAFENIBChEMBLPhase 4 (approved)RAF1
VANDETANIBChEMBLPhase 4 (approved)MAP2K1
CANERTINIBChEMBLPhase 3MAP2K1
DOVITINIBChEMBLPhase 3MAP2K1
LESTAURTINIBChEMBLPhase 3MAP2K1
LINSITINIBChEMBLPhase 3MAP2K1
MOTESANIBChEMBLPhase 3RAF1
NAPORAFENIBChEMBLPhase 3RAF1
ORANTINIBChEMBLPhase 3MAP2K1
PLINABULINChEMBLPhase 3RAF1
SARACATINIBChEMBLPhase 3MAP2K1
BELVARAFENIBChEMBLPhase 2RAF1
BRIMARAFENIBChEMBLPhase 2RAF1
CENISERTIBChEMBLPhase 2MAP2K1
DEFOSBARASERTIBChEMBLPhase 2MAP2K1
DORAMAPIMODChEMBLPhase 2RAF1
E-6201ChEMBLPhase 2MAP2K1
EXARAFENIBChEMBLPhase 2RAF1
ILORASERTIBChEMBLPhase 2MAP2K1
MIRDAMETINIBChEMBLPhase 2MAP2K1
PELITINIBChEMBLPhase 2MAP2K1
PIMASERTIBChEMBLPhase 2MAP2K1
RAF-265ChEMBLPhase 2RAF1
REBASTINIBChEMBLPhase 2RAF1
REFAMETINIBChEMBLPhase 2MAP2K1
RISOVALISIBChEMBLPhase 2RAF1
SOTRASTAURINChEMBLPhase 2MAP2K1
SU-014813ChEMBLPhase 2MAP2K1
TAK-733ChEMBLPhase 2MAP2K1
TOZASERTIBChEMBLPhase 2MAP2K1
ZAPNOMETINIBChEMBLPhase 2MAP2K1
dacomitinibPubChemApprovedMAP2K1
FostamatinibPubChemApprovedMAP2K1

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.4
BioBTree
v2.0.2

Sources 30

This page pulls from 30 datasets indexed by BioBTree:

chebichembl_activitychembl_moleculechembl_targetcivic_evidenceclingen_dosageclinical_trialsdepmapefoensemblentrezgogoparentgtopdbgtopdb_interactiongtopdb_ligandhgncmeshmondomsigdbpatent_compoundpharmgkbpharmgkb_guidelinepubchempubchem_activityreactomereactomeparentrefseqtranscriptuniprot