Identification

Summary

Futibatinib is a kinase inhibitor used to treat intrahepatic cholangiocarcinoma in previously treated adults.

Generic Name
Futibatinib
DrugBank Accession Number
DB15149
Background

Futibatinib is an inhibitor of Fibroblast Growth Factor receptor (FGFR), which comprises a group of receptor tyrosine kinases that play a key role in cell proliferation, differentiation, migration, and survival. FGFR was investigated in oncology as a therapeutic target, as FGFR genomic aberrations and dysregulated FGFR signalling pathways are observed in some cancers such as cholangiocarcinoma and urothelial malignancies.1,2

As a novel inhibitor of FGFR, futibatinib was first approved by the FDA in September 2022 to treat different types of intrahepatic cholangiocarcinoma.4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 418.457
Monoisotopic: 418.175338592
Chemical Formula
C22H22N6O3
Synonyms
  • 1-((3S)-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo(3, 4-d) pyrimidin-1-yl)-1-pyrrolidinyl)-2-propen-1-one
  • 1-[(3S)-3-{4-amino-3-[(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}pyrrolidin-1-yl]prop-2-en-1-one
  • Futibatinib
External IDs
  • TAS-120

Pharmacology

Indication

Futibatinib is indicated to treat adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.4

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).4

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Futibatinib is an anticancer agent with demonstrated anti-tumour activity in mouse and rat xenograft models of human tumours with activating FGFR genetic alterations.4 Futibatinib is not expected to affect cell lines with no FGFR genomic aberrations.2 It suppresses the growth of tumours in a dose-dependent manner.2

Mechanism of action

Fibroblast Growth Factor receptor (FGFR) pathway play a key role in cell proliferation, differentiation, migration, and survival. Notably, FGFR genomic aberrations and aberrant FGFR signalling pathways are observed in some cancers,1,2 as constitutive FGFR signalling can support the proliferation and survival of malignant cells.4

Futibatinib is a selective, irreversible inhibitor of FGFR 1, 2, 3, and 4 with IC50 values of less than 4 nM.2,4 It binds to the FGFR kinase domain by forming a covalent bond with cysteine in the ATP-binding pocket.2 Upon binding to FGFR, futibatinib blocks FGFR phosphorylation and downstream signalling pathways,4 such as the RAS-dependent mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3KCA)/Akt/mTOR, phospholipase Cγ (PLCγ), and JAK/STAT.3 Futibatinib ultimately decreases cell viability in cancer cell lines with FGFR alterations, including FGFR fusions or rearrangements, amplifications, and mutations.4

TargetActionsOrganism
AFibroblast growth factor receptor 1
inhibitor
Humans
AFibroblast growth factor receptor 2
inhibitor
Humans
AFibroblast growth factor receptor 3
inhibitor
Humans
AFibroblast growth factor receptor 4
inhibitor
Humans
Absorption

Tmax ranges from 1.2 to 22.8 hours, with a median value of two hours. In healthy subjects, a high-fat and high-calorie meal (900 to 1000 calories with approximately 50% of total caloric content from fat) decreased futibatinib AUC by 11% and Cmax by 42%.4

Volume of distribution

The geometric mean (CV%) apparent volume of distribution (Vc/F) is 66 L (18%).4

Protein binding

Futibatinib is 95% bound to human plasma protein at 0.2 to 5 µmol/L in vitro, primarily to albumin and α1-acid glycoprotein.4

Metabolism

In vitro, futibatinib is primarily metabolized by CYP3A and to a lesser extent by CYP2C9 and CYP2D6. Unchanged futibatinib is the major drug-related moiety in plasma (accounting for 59% of radioactivity) in healthy subjects.4

Route of elimination

Following a single oral dose of 20 mg radiolabeled futibatinib, approximately 91% of the total recovered radioactivity was observed in feces and 9% in urine, with negligible unchanged futibatinib in urine or feces.4

Half-life

The mean (CV%) elimination half-life (t1/2) of futibatinib is 2.9 hours (27%).4

Clearance

The geometric mean (CV%) apparent clearance (CL/F) is 20 L/h (23%).4

Adverse Effects
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Toxicity

There is no information available regarding acute toxicity and overdose of futibatinib.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Futibatinib can be increased when it is combined with Abametapir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Futibatinib.
AbrocitinibThe serum concentration of Futibatinib can be increased when it is combined with Abrocitinib.
AfatinibThe serum concentration of Futibatinib can be increased when it is combined with Afatinib.
AmbrisentanThe serum concentration of Futibatinib can be increased when it is combined with Ambrisentan.
AmiodaroneThe metabolism of Futibatinib can be decreased when combined with Amiodarone.
AmprenavirThe metabolism of Futibatinib can be decreased when combined with Amprenavir.
ApalutamideThe metabolism of Futibatinib can be increased when combined with Apalutamide.
ApixabanThe serum concentration of Futibatinib can be increased when it is combined with Apixaban.
AprepitantThe metabolism of Futibatinib can be decreased when combined with Aprepitant.
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Food Interactions
  • Take at the same time every day.
  • Take with or without food. A high-fat and high-calorie meal decreases drug exposure, but not to a clinically significant extent.

Categories

ATC Codes
L01EN04 — Futibatinib
Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
4B93MGE4AL
CAS number
1448169-71-8
InChI Key
KEIPNCCJPRMIAX-HNNXBMFYSA-N
InChI
InChI=1S/C22H22N6O3/c1-4-19(29)27-8-7-15(12-27)28-22-20(21(23)24-13-25-22)18(26-28)6-5-14-9-16(30-2)11-17(10-14)31-3/h4,9-11,13,15H,1,7-8,12H2,2-3H3,(H2,23,24,25)/t15-/m0/s1
IUPAC Name
1-[(3S)-3-{4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}pyrrolidin-1-yl]prop-2-en-1-one
SMILES
COC1=CC(=CC(OC)=C1)C#CC1=NN([C@H]2CCN(C2)C(=O)C=C)C2=C1C(N)=NC=N2

References

General References
  1. Kommalapati A, Tella SH, Borad M, Javle M, Mahipal A: FGFR Inhibitors in Oncology: Insight on the Management of Toxicities in Clinical Practice. Cancers (Basel). 2021 Jun 13;13(12). pii: cancers13122968. doi: 10.3390/cancers13122968. [Article]
  2. Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, Miura A, Sagara T, Ito S, Ohsawa H, Otsuki S, Funabashi K, Yashiro M, Matsuo K, Yonekura K, Hirai H: Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020 Nov 15;80(22):4986-4997. doi: 10.1158/0008-5472.CAN-19-2568. Epub 2020 Sep 24. [Article]
  3. Rizzo A, Ricci AD, Brandi G: Futibatinib, an investigational agent for the treatment of intrahepatic cholangiocarcinoma: evidence to date and future perspectives. Expert Opin Investig Drugs. 2021 Apr;30(4):317-324. doi: 10.1080/13543784.2021.1837774. Epub 2020 Oct 25. [Article]
  4. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]
ChemSpider
58877816
BindingDB
161389
ChEMBL
CHEMBL3701238
ZINC
ZINC000207800318
PDBe Ligand
TZ0
Wikipedia
Futibatinib
PDB Entries
6mzq / 6mzw / 7d5o

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Not Yet RecruitingTreatmentBiliary Tract Neoplasms1
3RecruitingHealth Services ResearchSoft Tissue Sarcoma (STS)1
3RecruitingTreatmentCholangiocarcinoma Advanced / FGFR2 Gene Rearrangements1
2Active Not RecruitingTreatmentAdvanced or Metastatic Gastric or Gastroesophageal Cancer / Advanced or Metastatic Solid Tumors / Myeloid/lymphoid neoplasms1
2RecruitingTreatmentAdvanced and Metastatic Urothelial Cancer1
2RecruitingTreatmentAdvanced Hepatocellular Carcinoma (HCC) / BCLC Stage A Hepatocellular Carcinoma / BCLC Stage B Hepatocellular Carcinoma / BCLC Stage C Hepatocellular Carcinoma / Metastatic Hepatocellular Carcinoma1
2RecruitingTreatmentEndometrial Cancer / Endometrial Carcinoma / Metastatic Cancers1
2RecruitingTreatmentFGFR 1 High Amplification / FGFR2 Amplification / Metastatic Breast Cancer1
1RecruitingTreatmentAdvanced or Metastatic Solid Tumors / Colorectal Cancer / Non-Small Cell Lung Carcinoma (NSCLC) / Pancreatic Adenocarcinoma (Ductal Adenocarcinoma)1
1, 2Active Not RecruitingTreatmentAdvanced and Metastatic Cancer Patients With Tumors Harboring FGF/FGFR Tumors / Breast Cancer / Cholangiocarcinoma / Malignant Neoplasm of Stomach / Primary CNS Tumors / Urothelial Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0398 mg/mLALOGPS
logP1.79ALOGPS
logP1.77Chemaxon
logS-4ALOGPS
pKa (Strongest Acidic)19.22Chemaxon
pKa (Strongest Basic)2.58Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area108.39 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity122.82 m3·mol-1Chemaxon
Polarizability45.57 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation ...
Gene Name
FGFR1
Uniprot ID
P11362
Uniprot Name
Fibroblast growth factor receptor 1
Molecular Weight
91866.935 Da
References
  1. Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, Miura A, Sagara T, Ito S, Ohsawa H, Otsuki S, Funabashi K, Yashiro M, Matsuo K, Yonekura K, Hirai H: Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020 Nov 15;80(22):4986-4997. doi: 10.1158/0008-5472.CAN-19-2568. Epub 2020 Sep 24. [Article]
  2. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosi...
Gene Name
FGFR2
Uniprot ID
P21802
Uniprot Name
Fibroblast growth factor receptor 2
Molecular Weight
92024.29 Da
References
  1. Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, Miura A, Sagara T, Ito S, Ohsawa H, Otsuki S, Funabashi K, Yashiro M, Matsuo K, Yonekura K, Hirai H: Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020 Nov 15;80(22):4986-4997. doi: 10.1158/0008-5472.CAN-19-2568. Epub 2020 Sep 24. [Article]
  2. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an...
Gene Name
FGFR3
Uniprot ID
P22607
Uniprot Name
Fibroblast growth factor receptor 3
Molecular Weight
87708.905 Da
References
  1. Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, Miura A, Sagara T, Ito S, Ohsawa H, Otsuki S, Funabashi K, Yashiro M, Matsuo K, Yonekura K, Hirai H: Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020 Nov 15;80(22):4986-4997. doi: 10.1158/0008-5472.CAN-19-2568. Epub 2020 Sep 24. [Article]
  2. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein tyrosine kinase activity
Specific Function
Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation o...
Gene Name
FGFR4
Uniprot ID
P22455
Uniprot Name
Fibroblast growth factor receptor 4
Molecular Weight
87953.535 Da
References
  1. Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, Miura A, Sagara T, Ito S, Ohsawa H, Otsuki S, Funabashi K, Yashiro M, Matsuo K, Yonekura K, Hirai H: Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020 Nov 15;80(22):4986-4997. doi: 10.1158/0008-5472.CAN-19-2568. Epub 2020 Sep 24. [Article]
  2. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: LYTGOBI (futibatinib) tablets, for oral use [Link]

Drug created at May 20, 2019 14:54 / Updated at December 01, 2022 11:29