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Navtemadlin

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Also known as AMG 232AMG-232Krt-232Mdm2 inhibitor amg-232AMG232

Summary

Navtemadlin (CHEMBL3125702) is a phase-3 clinical-stage small molecule targeting MDM2; indicated across 18 conditions including essential thrombocythemia and acquired polycythemia vera; with CIViC clinical evidence for 2 variant-indication associations (e.g. MDM2 Amplification in glioblastoma).

At a glance

  • Status: Max clinical phase 3 (not approved)
  • Modality: Small molecule
  • Targets: 1 (MDM2)
  • Indications: 18 conditions
  • Clinical trials: 20
  • Precision-oncology evidence (CIViC): 2 variant–indication associations
  • Chemistry: 568.6 Da · C28H35Cl2NO5S

Identifiers

Drug identity and classification

FieldValue
ChEMBL IDCHEMBL3125702
NameNavtemadlin
TypeSmall molecule
Max phase3
FDA approvedno
PubChem CID58573469
Molecular formulaC28H35Cl2NO5S
Molecular weight568.6
InChIKeyDRLCSJFKKILATL-YWCVFVGNSA-N

SMILES: CC(C)[C@@H](CS(=O)(=O)C(C)C)N1[C@@H]([C@H](C[C@](C1=O)(C)CC(=O)O)C2=CC(=CC=C2)Cl)C3=CC=C(C=C3)Cl

IUPAC name: 2-[(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2S)-3-methyl-1-propan-2-ylsulfonylbutan-2-yl]-2-oxopiperidin-3-yl]acetic acid

Also known as: AMG 232, Amg 232, AMG-232, Krt-232, KRT-232, Mdm2 inhibitor amg-232, Navtemadlin, AMG232, NAVTEMADLIN, MDM2 INHIBITOR AMG-232

Patent coverage: 408 distinct patent families (1,107 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 1,100 (99%) 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
MDM2MDM2 proto-oncogeneInhibition10.3538.4%Q00987

Broader ChEMBL bioactivity targets: 2 (assay-derived). Sample: Tumour suppressor p53/oncoprotein Mdm2, E3 ubiquitin-protein ligase Mdm2.

Bioactivity

ChEMBL activities: 11 potent at pChembl ≥ 5 of 11 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

TargetpChemblTypeValueUnitActivity ID
MDM210.42Kd0.04nMCHEMBL_ACT_15190451
MDM210.35Kd0.04nMCHEMBL_ACT_13953123
MDM210.35Kd0.04nMCHEMBL_ACT_15190452
MDM29.22IC500.6nMCHEMBL_ACT_13951897
MDM29.22IC500.6nMCHEMBL_ACT_19044306
TP539.22IC500.6nMCHEMBL_ACT_24915496
TP539.22IC500.6nMCHEMBL_ACT_25030020
MDM29.2IC500.63nMCHEMBL_ACT_15190390
TP539IC501nMCHEMBL_ACT_17752386
MDM29IC501nMCHEMBL_ACT_27011198
MDM27.33IC5047nMCHEMBL_ACT_15190366

Target pathways

Aggregated over 1 target gene(s): MDM2.

Top Reactome pathways

48 total, by targets touching each:

PathwayTargetsGenes
Neurotransmitter receptors and postsynaptic signal transmission1MDM2
Transmission across Chemical Synapses1MDM2
Neuronal System1MDM2
PIP3 activates AKT signaling1MDM2
Signal Transduction1MDM2
Cell Cycle1MDM2
Disease1MDM2
AKT phosphorylates targets in the cytosol1MDM2
Generic Transcription Pathway1MDM2
PI3K/AKT Signaling in Cancer1MDM2
Cellular responses to stress1MDM2
Oxidative Stress Induced Senescence1MDM2
Cellular Senescence1MDM2
Oncogene Induced Senescence1MDM2
SUMOylation1MDM2
SUMO E3 ligases SUMOylate target proteins1MDM2
SUMOylation of transcription factors1MDM2
SUMOylation of ubiquitinylation proteins1MDM2
Transcriptional Regulation by TP531MDM2
Metabolism of proteins1MDM2
Trafficking of AMPA receptors1MDM2
Glutamate binding, activation of AMPA receptors and synaptic plasticity1MDM2
Regulation of TP53 Activity1MDM2
Diseases of signal transduction by growth factor receptors and second messengers1MDM2
Constitutive Signaling by AKT1 E17K in Cancer1MDM2
Deubiquitination1MDM2
Ub-specific processing proteases1MDM2
Post-translational protein modification1MDM2
Regulation of TP53 Activity through Phosphorylation1MDM2
Regulation of TP53 Degradation1MDM2
Regulation of TP53 Activity through Methylation1MDM2
Regulation of TP53 Expression and Degradation1MDM2
Stabilization of p531MDM2
p53-Dependent G1 DNA Damage Response1MDM2
p53-Dependent G1/S DNA damage checkpoint1MDM2
G1/S DNA Damage Checkpoints1MDM2
Cell Cycle Checkpoints1MDM2
RNA Polymerase II Transcription1MDM2
Gene expression (Transcription)1MDM2
Transcriptional regulation by RUNX31MDM2
Regulation of RUNX3 expression and activity1MDM2
Cellular responses to stimuli1MDM2
Intracellular signaling by second messengers1MDM2
Transcriptional Regulation by NPAS41MDM2
Signaling by ALK in cancer1MDM2
Signaling by ALK fusions and activated point mutants1MDM2
Degradation of CDH11MDM2
NPAS4 regulates expression of target genes1MDM2

Dominant GO biological processes

GO termTargets
negative regulation of transcription by RNA polymerase II1
protein polyubiquitination1
blood vessel development1
blood vessel remodeling1
regulation of heart rate1
atrioventricular valve morphogenesis1
endocardial cushion morphogenesis1
ventricular septum development1
atrial septum development1
ubiquitin-dependent protein catabolic process1
apoptotic process1
traversing start control point of mitotic cell cycle1
positive regulation of cell population proliferation1
response to xenobiotic stimulus1
response to toxic substance1

Indications & clinical

Indications

15 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
essential thrombocythemia2MONDO:0005029EFO:0000479
acquired polycythemia vera2MONDO:0009891EFO:0002429
primary myelofibrosis2MONDO:0009692EFO:0002430
small cell lung carcinoma2MONDO:0008433EFO:0000702
endometrium neoplasm2MONDO:0021251MONDO:0011962
acute myeloid leukemia1MONDO:0018874EFO:0000222
gliosarcoma1MONDO:0016681EFO:1001465
soft tissue sarcoma1MONDO:0018078EFO:1001968
plasma cell myeloma1MONDO:0009693EFO:0001378
plasmacytoma1MONDO:0005615EFO:0006738
cutaneous neuroendocrine carcinoma1MONDO:0019210EFO:1001471
chronic myeloid leukemia1MONDO:0011996EFO:0000339
melanoma1MONDO:0005105EFO:0000756
neoplasm1MONDO:0005070EFO:0000616
non-small cell lung carcinoma1MONDO:0005233EFO:0003060

3 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 20.

Phase distribution

PhaseTrials
PHASE1/PHASE29
PHASE15
PHASE23
PHASE2/PHASE32
PHASE31

Top trials by phase / activity

NCTPhaseStatusTitle
NCT05797831PHASE2/PHASE3RECRUITINGStudy of Navtemadlin as Maintenance Therapy in TP53WT Advanced or Recurrent Endometrial Cancer
NCT06479135PHASE3RECRUITINGStudy of Navtemadlin add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib
NCT03662126PHASE2/PHASE3UNKNOWNKRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment
NCT04835584PHASE1/PHASE2RECRUITINGKRT-232 and TKI Study in Chronic Myeloid Leukemia
NCT02825836PHASE1/PHASE2UNKNOWNPhase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects
NCT03669965PHASE2UNKNOWNKRT-232 Compared to Ruxolitinib in Patients With Phlebotomy-Dependent Polycythemia Vera
NCT03787602PHASE1/PHASE2UNKNOWNNavtemadlin (KRT-232) With or Without Anti-PD-1/Anti-PD-L1 for the Treatment of Patients With Merkel Cell Carcinoma
NCT04113616PHASE1/PHASE2TERMINATEDAn Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 When Administered Alone and in Combination With Low-Dose Cytarabine (LDAC) or Decitabine in Patients With Acute Myeloid Leukemia (AML)
NCT04485260PHASE1/PHASE2UNKNOWNAn Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined With Ruxolitinib in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV-MF), Or Post-Essential Thrombocythemia MF (Post ET-MF) Who Have a Suboptimal Response to Ruxolitinib
NCT04502394PHASE1/PHASE2UNKNOWNSafety and Efficacy of KRT-232 in Combination With Acalabrutinib in Subjects With R/R DLBCL or R/R CLL
NCT04640532PHASE1/PHASE2UNKNOWNKRT-232 in Combination With TL-895 for the Treatment of R/R MF and KRT-232 for the Treatment of JAKi Intolerant MF
NCT04669067PHASE1/PHASE2UNKNOWNTL-895 and KRT-232 Study in Acute Myeloid Leukemia
NCT04878003PHASE2UNKNOWNStudy of KRT-232 or TL-895 in Janus Associated Kinase Inhibitor Treatment-Naïve Myelofibrosis
NCT05027867PHASE2TERMINATEDKRT-232 in Subjects With Relapsed or Refractory Small Cell Lung Cancer
NCT05705466PHASE1/PHASE2WITHDRAWNStudy of Navtemadlin Plus Pembrolizumab as Maintenance Therapy in Locally Advanced and Metastatic Non-Small Cell Lung Cancer
NCT03041688PHASE1ACTIVE_NOT_RECRUITINGTesting a New Chemotherapy Drug, KRT-232 (AMG-232) in Combination With Decitabine and Venetoclax in Patients With Acute Myeloid Leukemia
NCT04190550PHASE1ACTIVE_NOT_RECRUITINGTesting the Addition of an Anti-cancer Drug, Navtemadlin, to the Usual Treatments (Cytarabine and Idarubicin) in Patients With Acute Myeloid Leukemia
NCT03031730PHASE1TERMINATEDTesting the Addition of KRT-232 (AMG 232) to Usual Chemotherapy for Relapsed Multiple Myeloma
NCT03107780PHASE1TERMINATEDTesting the Ability of AMG 232 (KRT 232) to Get Into the Tumor in Patients With Brain Cancer
NCT03217266PHASE1COMPLETEDNavtemadlin and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma

Clinical evidence (CIViC)

Variant × indication × effect (2 predictive associations from 2 curated evidence items):

VariantIndicationEffectTherapyLevelCIViC
MDM2 AmplificationGlioblastomaSensitivity/ResponseNavtemadlin + RG7112CIViC DEID9023
MDM2 EXPRESSIONOvarian CancerSensitivity/ResponseNavtemadlinCIViC DEID9852

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

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.

10 molecules share ≥1 primary target. Top 10 by shared-target count:

MoleculeSourceStatusShared targets
APOMORPHINEChEMBLPhase 4 (approved)MDM2
CYTARABINEChEMBLPhase 4 (approved)MDM2
NITROFURANTOINChEMBLPhase 4 (approved)MDM2
BRIGIMADLINChEMBLPhase 3MDM2
IDASANUTLINChEMBLPhase 3MDM2
MILADEMETANChEMBLPhase 3MDM2
ALRIZOMADLINChEMBLPhase 2MDM2
SIREMADLINChEMBLPhase 2MDM2
THIRAMChEMBLPhase 2MDM2
CarfilzomibPubChemApprovedMDM2

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