regorafenib Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definitionDrug idCAS RN
Raf (Rapidely Accelerated Fibrosarcoma) kinase inhibitors 4654 755037-03-7

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • regorafenib monohydrate
  • Stivarga
  • regorafenib
  • regorafenib hydrate
  • anhydrous regorafenib
  • BAY 73-4506
Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl and CSF1R at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma. Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma.
  • Molecular weight: 482.82
  • Formula: C21H15ClF4N4O3
  • CLOGP: 5.19
  • LIPINSKI: 1
  • HAC: 7
  • HDO: 3
  • TPSA: 92.35
  • ALOGS: -5.67
  • ROTB: 6

  • Status: ONP

  • Legend:
    OFP - off patent
    OFM - off market
    ONP - on patent

Drug dosage:

DoseUnitRoute
0.12 g O

ADMET properties:

None

Approvals:

DateAgencyCompanyOrphan
Aug. 26, 2013 EMA
Sept. 27, 2012 FDA BAYER HLTHCARE

FDA Adverse Event Reporting System (Female)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Palmar-plantar erythrodysaesthesia syndrome 1120.61 26.37 340 11425 21266 53316035
Dysphonia 410.19 26.37 195 11570 41743 53295558
Colorectal cancer metastatic 381.08 26.37 76 11689 771 53336530
Colon cancer 293.47 26.37 102 11663 9723 53327578
Colorectal cancer 283.58 26.37 65 11700 1327 53335974
Off label use 236.69 26.37 393 11372 471819 52865482
Decreased appetite 233.56 26.37 261 11504 214713 53122588
Hepatocellular carcinoma 200.76 26.37 58 11707 3022 53334279
Metastases to lung 160.50 26.37 69 11696 11635 53325666
Fatigue 152.40 26.37 426 11339 730080 52607221
Blister 118.27 26.37 114 11651 78639 53258662
Hyperkeratosis 105.61 26.37 41 11724 5325 53331976
Skin exfoliation 103.66 26.37 76 11689 36007 53301294
Metastases to liver 99.71 26.37 61 11704 21435 53315866
Carcinoembryonic antigen increased 95.61 26.37 28 11737 1529 53335772
Diarrhoea 95.60 26.37 328 11437 625218 52712083
Asthenia 93.33 26.37 222 11543 343368 52993933
Pyrexia 92.26 26.37 244 11521 402949 52934352
Pain in extremity 89.36 26.37 195 11570 284855 53052446
Gastrointestinal stromal tumour 89.02 26.37 25 11740 1174 53336127
Hypertension 86.88 26.37 168 11597 225263 53112038
Neuropathy peripheral 86.40 26.37 110 11655 103077 53234224
Rectal cancer 85.69 26.37 27 11738 1890 53335411
Blood bilirubin increased 84.44 26.37 67 11698 35663 53301638
Stomatitis 79.60 26.37 103 11662 98055 53239246
Oral pain 73.63 26.37 55 11710 26782 53310519
Weight decreased 68.22 26.37 156 11609 234792 53102509
Dehydration 66.63 26.37 127 11638 168283 53169018
Dry skin 64.44 26.37 64 11701 45696 53291605
Rash 63.57 26.37 229 11536 445962 52891339
Blood pressure increased 61.91 26.37 111 11654 140368 53196933
Platelet count decreased 57.64 26.37 93 11672 108006 53229295
Hepatic function abnormal 48.99 26.37 50 11715 36849 53300452
Hospitalisation 47.63 26.37 68 11697 70944 53266357
Drug ineffective 46.49 26.37 68 11697 817177 52520124
Skin fissures 46.21 26.37 27 11738 8718 53328583
Condition aggravated 45.33 26.37 6 11759 297128 53040173
Colon cancer metastatic 45.06 26.37 15 11750 1250 53336051
Disseminated intravascular coagulation 44.48 26.37 36 11729 19683 53317618
Erythema 43.04 26.37 102 11663 156867 53180434
Mucosal inflammation 42.88 26.37 50 11715 42734 53294567
Gait inability 42.17 26.37 47 11718 38264 53299037
Plantar erythema 41.23 26.37 10 11755 262 53337039
Tumour marker increased 40.44 26.37 19 11746 3934 53333367
Dry mouth 38.43 26.37 56 11709 59494 53277807
Exercise tolerance decreased 38.00 26.37 20 11745 5275 53332026
Palmoplantar keratoderma 37.79 26.37 8 11757 111 53337190
Abdominal pain 37.70 26.37 133 11632 255770 53081531
Skin toxicity 36.79 26.37 18 11747 4075 53333226
Hepatic encephalopathy 31.44 26.37 23 11742 10836 53326465
Drug hypersensitivity 30.93 26.37 10 11755 265232 53072069
Feeding disorder 28.33 26.37 22 11743 11332 53325969
Drug interaction 27.91 26.37 7 11758 219322 53117979
Constipation 26.55 26.37 100 11665 198312 53138989
Jaundice 26.40 26.37 33 11732 30280 53307021

FDA Adverse Event Reporting System (Male)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Palmar-plantar erythrodysaesthesia syndrome 1870.55 23.38 560 14985 15189 32482792
Hepatocellular carcinoma 739.39 23.38 250 15295 10020 32487961
Dysphonia 712.38 23.38 293 15252 20391 32477590
Colorectal cancer 499.53 23.38 131 15414 2122 32495859
Colorectal cancer metastatic 471.64 23.38 109 15436 1008 32496973
Colon cancer 319.77 23.38 130 15415 8736 32489245
Decreased appetite 316.81 23.38 386 15159 160427 32337554
Metastases to lung 308.99 23.38 125 15420 8292 32489689
Off label use 300.32 23.38 528 15017 305792 32192189
Fatigue 254.29 23.38 532 15013 350169 32147812
Blister 192.39 23.38 124 15421 21967 32476014
Diarrhoea 187.55 23.38 484 15061 364318 32133663
Metastases to liver 176.48 23.38 97 15448 12835 32485146
Gastrointestinal stromal tumour 165.33 23.38 49 15496 1261 32496720
Carcinoembryonic antigen increased 149.52 23.38 40 15505 700 32497281
Hypertension 141.01 23.38 237 15308 131513 32366468
Pain in extremity 132.71 23.38 218 15327 118683 32379298
Rectal cancer 125.06 23.38 46 15499 2351 32495630
Skin exfoliation 115.66 23.38 96 15449 25061 32472920
Blood bilirubin increased 110.06 23.38 113 15432 38671 32459310
Skin fissures 103.35 23.38 46 15499 3857 32494124
Asthenia 98.61 23.38 291 15254 235653 32262328
Dry skin 95.91 23.38 86 15459 24892 32473089
Neuropathy peripheral 93.76 23.38 147 15398 76835 32421146
Weight decreased 86.36 23.38 221 15324 164597 32333384
Hyperkeratosis 85.42 23.38 39 15506 3470 32494511
Stomatitis 82.65 23.38 99 15446 40130 32457851
Alpha 1 foetoprotein increased 82.02 23.38 25 15520 709 32497272
Tumour marker increased 79.39 23.38 23 15522 545 32497436
Ascites 73.04 23.38 93 15452 40098 32457883
Blood pressure increased 70.80 23.38 132 15413 79222 32418759
Hospitalisation 61.63 23.38 95 15450 48876 32449105
Hepatic function abnormal 59.27 23.38 89 15456 44751 32453230
Oral pain 58.58 23.38 44 15501 9934 32488047
Colon cancer metastatic 57.01 23.38 24 15521 1756 32496225
Hepatic encephalopathy 50.76 23.38 48 15497 14847 32483134
Toxicity to various agents 47.86 23.38 13 15532 178028 32319953
Abdominal pain 44.78 23.38 165 15380 149364 32348617
Abdominal pain upper 44.55 23.38 99 15446 67239 32430742
Dehydration 44.38 23.38 149 15396 128809 32369172
Glossodynia 44.19 23.38 25 15520 3491 32494490
Metastases to lymph nodes 43.87 23.38 27 15518 4401 32493580
Drug interaction 43.81 23.38 25 15520 218160 32279821
Aphonia 43.29 23.38 24 15521 3222 32494759
Febrile neutropenia 40.07 23.38 5 15540 119561 32378420
Colorectal cancer recurrent 39.92 23.38 8 15537 34 32497947
Metastases to peritoneum 38.93 23.38 18 15527 1648 32496333
Acute kidney injury 36.95 23.38 52 15493 293416 32204565
Dry mouth 36.41 23.38 51 15494 24068 32473913
Colon cancer recurrent 35.25 23.38 9 15536 130 32497851
Drug ineffective 34.10 23.38 84 15461 383393 32114588
Hypotension 32.82 23.38 33 15512 216077 32281904
Condition aggravated 32.43 23.38 17 15528 155644 32342337
Malaise 31.99 23.38 168 15377 176970 32321011
Cardiac arrest 30.20 23.38 5 15540 96771 32401210
Biliary obstruction 28.66 23.38 17 15528 2592 32495389
Overdose 28.31 23.38 4 15541 87073 32410908
Angular cheilitis 28.30 23.38 8 15537 173 32497808
Constipation 27.16 23.38 126 15419 126247 32371734
Proteinuria 26.64 23.38 37 15508 17318 32480663
Plantar erythema 25.61 23.38 6 15539 59 32497922
Protein induced by vitamin K absence or antagonist II increased 25.61 23.38 5 15540 18 32497963
Gait inability 25.35 23.38 39 15506 20008 32477973
Pneumonia 24.87 23.38 87 15458 355165 32142816
Neutropenia 24.83 23.38 19 15526 142156 32355825
Rectal cancer metastatic 24.50 23.38 8 15537 285 32497696
Rectal cancer stage IV 24.35 23.38 4 15541 3 32497978
Metastases to adrenals 23.73 23.38 11 15534 1013 32496968

Pharmacologic Action:

SourceCodeDescription
ATC L01EX05 ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
PROTEIN KINASE INHIBITORS
Other protein kinase inhibitors
FDA MoA N0000175076 Protein Kinase Inhibitors
FDA EPC N0000175605 Kinase Inhibitor
FDA MoA N0000185504 Cytochrome P450 2C9 Inhibitors
CHEBI has role CHEBI:35610 cytostatic
CHEBI has role CHEBI:38637 protein tyrosine kinase inhibitor
CHEBI has role CHEBI:50908 agente hepatotoxico

Drug Use (View source of the data)

DiseaseRelationSNOMED_IDDOID
Liver cell carcinoma indication 109841003 DOID:684
Metastasis from malignant tumor of colon indication 314998002
Gastrointestinal stromal tumor indication 420120006 DOID:9253

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 11.41 acidic
pKa2 11.83 acidic
pKa3 12.52 acidic
pKa4 2.76 Basic

Orange Book patent data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRoutePatent numberPatent expiration datePatent use
40MG STIVARGA BAYER HLTHCARE N203085 Sept. 27, 2012 RX TABLET ORAL 8680124 June 2, 2030 TREATMENT OF PATIENTS WITH GASTROINTESTINAL STROMAL TUMOR (GIST), INCLUDING BUT NOT LIMITED TO PATIENTS PREVIOUSLY TREATED WITH IMATINIB AND PATIENTS WITH GIST HAVING RESISTANCE TO A KIT TYROSINE KINASE INHIBITOR

Orange Book exclusivity data (new drug applications)

Formulation strengthTrade nameApplicantApplication numberApproval dateTypeDose formRouteExclusivity dateDescription
40MG STIVARGA BAYER HLTHCARE N203085 Sept. 27, 2012 RX TABLET ORAL April 27, 2024 TREATMENT OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC OR LIVER CANCER) WHO HAVE BEEN PREVIOUSLY TREATED WITH THE DRUG SORAFENIB.

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])
Mechanism
action
Bioact sourceMoA source
Serine/threonine-protein kinase B-raf Kinase INHIBITOR IC50 7.55 CHEMBL CHEMBL
Vascular endothelial growth factor receptor 2 Kinase INHIBITOR IC50 7.90 IUPHAR CHEMBL
Tyrosine-protein kinase ABL1 Kinase Kd 6.12 CHEMBL
Mast/stem cell growth factor receptor Kit Kinase IC50 8.21 CHEMBL
Breakpoint cluster region protein Kinase Kd 6.13 CHEMBL
Ephrin type-A receptor 2 Kinase Kd 6.08 CHEMBL
RAF proto-oncogene serine/threonine-protein kinase Kinase IC50 8.82 CHEMBL
Receptor-type tyrosine-protein kinase FLT3 Kinase IC50 7.09 CHEMBL
Proto-oncogene tyrosine-protein kinase receptor Ret Kinase Kd 6.90 CHEMBL
Vascular endothelial growth factor receptor 1 Kinase IC50 8.82 CHEMBL
Angiopoietin-1 receptor Kinase IC50 8.82 CHEMBL
LIM domain kinase 1 Kinase Kd 6.21 CHEMBL
Fibroblast growth factor receptor 1 Kinase IC50 8.82 CHEMBL
Dual specificity protein kinase TTK Kinase Kd 5.41 CHEMBL
Mitogen-activated protein kinase 11 Kinase Kd 5.72 CHEMBL
Ephrin type-A receptor 5 Kinase Kd 5.95 CHEMBL
Mitogen-activated protein kinase 14 Kinase Kd 6.15 CHEMBL
Dual specificity protein kinase CLK1 Kinase Kd 5.68 CHEMBL
Receptor-interacting serine/threonine-protein kinase 2 Kinase Kd 6.12 CHEMBL
Epithelial discoidin domain-containing receptor 1 Kinase Kd 6.45 CHEMBL
Bifunctional epoxide hydrolase 2 Enzyme INHIBITOR IC50 9.30 CHEMBL
MAP kinase-activated protein kinase 2 Kinase Kd 6.17 CHEMBL
Cyclin-dependent kinase 17 Kinase Kd 6.14 CHEMBL
Mitogen-activated protein kinase kinase kinase MLT Kinase Kd 6.56 CHEMBL
Discoidin domain-containing receptor 2 Kinase Kd 6.38 CHEMBL
Ephrin type-A receptor 1 Kinase Kd 8.15 CHEMBL
Mitogen-activated protein kinase kinase kinase 1 Kinase Kd 6.33 CHEMBL
Glycine receptor subunit alpha-1 Ion channel EC50 5.74 CHEMBL
Receptor-interacting serine/threonine-protein kinase 3 Kinase Kd 6.43 CHEMBL
Platelet-derived growth factor receptor beta Kinase IC50 8.82 CHEMBL
Vascular endothelial growth factor receptor 2 Kinase IC50 8.82 CHEMBL
Vascular endothelial growth factor receptor 3 Kinase IC50 8.82 CHEMBL

External reference:

IDSource
D10137 KEGG_DRUG
1019206-88-2 SECONDARY_CAS_RN
4031721 VANDF
CHEBI:68647 CHEBI
CHEMBL1946170 ChEMBL_ID
C559147 MESH_SUPPLEMENTAL_RECORD_UI
5891 IUPHAR_LIGAND_ID
DB08896 DRUGBANK_ID
MGN125FS9D UNII
11167602 PUBCHEM_CID
1312397 RXNORM
193440 MMSL
28887 MMSL
d07913 MMSL
014656 NDDF
702804006 SNOMEDCT_US
703808002 SNOMEDCT_US
C2980094 UMLSCUI

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Stivarga HUMAN PRESCRIPTION DRUG LABEL 1 50419-171 TABLET, FILM COATED 40 mg ORAL NDA 29 sections