Identification

Name
Entrectinib
Accession Number
DB11986
Description

Entrectinib is a tropomyosin receptor tyrosine kinase (TRK) TRKA, TRKB, TRKC, proto-oncogene tyrosine-protein kinase ROS1, and anaplastic lymphoma kinase (ALK) inhibitor.7 It was approved by the FDA in August 2019 for use in the treatment of ROS1-positive metastatic non-small cell lung cancer and NTRK gene fusion positive solid tumors.9 Entrectinib's approved use is meant as a last line of therapy due to its accelerated approval based on early trial data. This therapy offers benefit over similar ALK inhibitors such as alectinib, ceritinib, and lorlatinib due to a wider range of targets.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 560.65
Monoisotopic: 560.271130685
Chemical Formula
C31H34F2N6O2
Synonyms
  • Entrectinib
External IDs
  • RXDX-101

Pharmacology

Indication

Entrectinib is indicated for the treatment of metastatic ROS1-positive non-small cell lung cancer in adults.7 Entrectinib is also indicated in adults and children over 12 years old for the treatment of NTRK gene fusion-positive solid tumors which have metastasized or for which surgical resection is likely to result in severe morbidity and for which has progressed on previous therapies or for which no comparable alternative therapies are available.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Entrectinib and its active metabolite suppress several pathways which contribute to cell survival and proliferation.2,4,5,6,7 This suppression shifts the balance in favor of apoptosis thereby preventing cancer cell growth and shrinking tumors.

Mechanism of action

Entrectinib is a tyrosine kinase inhibitor which acts on several receptors. It functions as an ATP competitor to inhibit tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, as well as proto-oncogene tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK).4,5,7 TRK receptors produce cell proliferation via downstream signalling through the mitogen activated protein kinase, phosphoinositide 3-kinase, and phospholipase C-γ.4 ALK produces similar signalling with the addition of downstream JAK/STAT activation.6 Inhibition of these pathways suppresses cancer cell proliferation and shifts the balance in favor of apoptosis resulting in shrinking of tumor volume.5

TargetActionsOrganism
AHigh affinity nerve growth factor receptor
inhibitor
Humans
UBDNF/NT-3 growth factors receptor
inhibitor
Humans
ANT-3 growth factor receptor
inhibitor
Humans
AProto-oncogene tyrosine-protein kinase ROS
inhibitor
Humans
UTyrosine-protein kinase JAK2
inhibitor
Humans
UActivated CDC42 kinase 1Not AvailableHumans
Absorption

Entrectinib has a Tmax of 4-5 h after administration of a single 600 mg dose.7 Food does not produce a significant effect on the extent of absorption.

Volume of distribution

Entrectinib has an apparent volume of distribution of 551 L.7 The active metabolite, M5, has an apparent volume of distribution of 81.1 L. Entrectinib is known to cross the blood-brain barrier.4

Protein binding

Entrectinib is over 99% bound to plasma proteins.4,7

Metabolism

CYP3A4 is responsible for 76% of entrectinib metabolism in humans including metabolism to the active metabolite, M5.7 M5 has similar pharmacological activity to entrectinib and exists at approximately 40% of the steady state concentration of the parent drug. In rats, six in vivo metabolites have been identified including N-dealkylated, N-oxide, hydroxylated, and glucuronide conjugated metabolites.3

Hover over products below to view reaction partners

Route of elimination

After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine.7 Of the dose in the feces, 36% was present as entrectinib and 22% as M5.

Half-life

Entrectinib has a half-life of elimination of 20 h.7 The active metabolite, M5, has a half-life of 40 h.

Clearance

The apparent clearance of entrectinib is 19.6 L/h while the apparent clearance of the active metabolite M5 is 52.4 L/h.7

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity
Not Available
Affected organisms
Not Available
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
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Entrectinib.
AbametapirThe serum concentration of Entrectinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Entrectinib can be increased when combined with Abatacept.
AcalabrutinibThe metabolism of Entrectinib can be decreased when combined with Acalabrutinib.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Entrectinib.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Entrectinib.
AcetazolamideThe metabolism of Entrectinib can be decreased when combined with Acetazolamide.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Entrectinib.
AdalimumabThe metabolism of Entrectinib can be increased when combined with Adalimumab.
AdenosineThe risk or severity of QTc prolongation can be increased when Adenosine is combined with Entrectinib.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of entrectinib.
  • Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of entrectinib.
  • Take with or without food. Co-administration of food does not affect pharmacokinetics.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RozlytrekCapsule100 mgOralHoffmann La Roche2020-03-10Not applicableCanada flag
RozlytrekCapsule200 mg/1OralGenentech Inc.2019-08-15Not applicableUS flag
RozlytrekCapsule200 mg/1OralGenentech Inc.2019-08-15Not applicableUS flag
RozlytrekCapsule100 mg/1OralGenentech Inc.2019-08-15Not applicableUS flag
RozlytrekCapsule200 mgOralHoffmann La Roche2020-03-04Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XE56 — Entrectinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
Phenylpiperazines
Alternative Parents
N-arylpiperazines / Aminobenzoic acids and derivatives / Anthranilamides / Indazoles / Aniline and substituted anilines / Benzoyl derivatives / Dialkylarylamines / Phenylalkylamines / Fluorobenzenes / Secondary alkylarylamines
show 16 more
Substituents
Amine / Amino acid or derivatives / Aminobenzoic acid or derivatives / Aniline or substituted anilines / Anthranilamide / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole
show 39 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
L5ORF0AN1I
CAS number
1108743-60-7
InChI Key
HAYYBYPASCDWEQ-UHFFFAOYSA-N
InChI
InChI=1S/C31H34F2N6O2/c1-38-8-10-39(11-9-38)25-3-4-26(29(19-25)34-24-6-12-41-13-7-24)31(40)35-30-27-17-20(2-5-28(27)36-37-30)14-21-15-22(32)18-23(33)16-21/h2-5,15-19,24,34H,6-14H2,1H3,(H2,35,36,37,40)
IUPAC Name
N-{5-[(3,5-difluorophenyl)methyl]-1H-indazol-3-yl}-4-(4-methylpiperazin-1-yl)-2-[(oxan-4-yl)amino]benzamide
SMILES
CN1CCN(CC1)C1=CC=C(C(=O)NC2=NNC3=CC=C(CC4=CC(F)=CC(F)=C4)C=C23)C(NC2CCOCC2)=C1

References

Synthesis Reference

US Patent 20190135784A1

General References
  1. Al-Salama ZT, Keam SJ: Entrectinib: First Global Approval. Drugs. 2019 Aug 1. pii: 10.1007/s40265-019-01177-y. doi: 10.1007/s40265-019-01177-y. [PubMed:31372957]
  2. Liu D, Offin M, Harnicar S, Li BT, Drilon A: Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252. doi: 10.2147/TCRM.S147381. eCollection 2018. [PubMed:30050303]
  3. Attwa MW, Kadi AA, Alrabiah H, Darwish HW: LC-MS/MS reveals the formation of iminium and quinone methide reactive intermediates in entrectinib metabolism: In vivo and in vitro metabolic investigation. J Pharm Biomed Anal. 2018 Oct 25;160:19-30. doi: 10.1016/j.jpba.2018.07.032. Epub 2018 Jul 22. [PubMed:30055343]
  4. Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, Giallombardo M, Peeters M, Raez L: Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493-500. doi: 10.1517/13543784.2015.1096344. Epub 2015 Oct 12. [PubMed:26457764]
  5. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A: Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016 Apr;15(4):628-39. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. [PubMed:26939704]
  6. Pacenta HL, Macy ME: Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Devel Ther. 2018 Oct 23;12:3549-3561. doi: 10.2147/DDDT.S147384. eCollection 2018. [PubMed:30425456]
  7. FDA Label: Rozlytrek [Link]
  8. Cayman Chemical: Entrectinib MSDS [Link]
  9. FDA Announcement: Entrectinib Approval [Link]
PubChem Compound
25141092
PubChem Substance
347828307
ChemSpider
24808589
BindingDB
158154
RxNav
2197862
ChEMBL
CHEMBL1983268
ZINC
ZINC000043204146
PDBe Ligand
YMX
Wikipedia
Entrectinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
5fto / 5kvt
FDA label
Download (830 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Not Yet RecruitingTreatmentER+ Breast Cancer / HER2 Negative Breast Cancer / HER2-Negative Breast Cancer / Invasive Lobular Breast Carcinoma1
2RecruitingTreatmentAdult Solid Tumor / Breast Cancer / Cholangiocarcinomas / Colorectal Cancers / Lymphoma, Large-Cell, Anaplastic / Malignant Neoplasm of Pancreas / Melanoma / Neoplasms, Head and Neck / Neuroendocrine Tumors / Non-Small Cell Lung Carcinoma (NSCLC) / Ovarian Cancer / Primary Brain Tumors / Renal Cell Adenocarcinoma / Salivary Gland Cancers / Sarcomas / Thyroid Papillary Carcinoma1
2RecruitingTreatmentCancer of Unknown Primary Site1
2RecruitingTreatmentCDK Gene Mutation / Metastatic Malignant Neoplasm in the Brain / Metastatic Malignant Solid Neoplasm / NTRK Family Gene Mutation / PI3K Gene Mutation / ROS1 Gene Mutation1
2RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2TerminatedTreatmentALK Fusion Protein Expression / BRAF wt Allele / Invasive Skin Melanoma / Melanoma / MET Fusion Gene Positive / NRAS wt Allele / NTRK1 Fusion Positive / NTRK2 Fusion Positive / NTRK3 Fusion Positive / RET Fusion Positive / ROS1 Fusion Positive / Stage III Cutaneous Melanoma / Stage III Cutaneous Melanoma AJCC v7 / Stage IIIA Cutaneous Melanoma / Stage IIIA Cutaneous Melanoma AJCC v7 / Stage IIIB Cutaneous Melanoma / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIC Cutaneous Melanoma / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IV Cutaneous Melanoma / Stage IV Cutaneous Melanoma AJCC v6 and v71
2, 3RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
1CompletedOtherAdvanced Solid Tumors1
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentLocally Advanced Solid Tumors / Metastatic Solid Tumors1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral100 mg/1
CapsuleOral100 mg
CapsuleOral200 mg/1
CapsuleOral200 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9616059No2017-04-112028-07-08US flag
US10231965No2019-03-192035-02-17US flag
US9649306No2017-05-162033-05-22US flag
US8673893No2014-03-182028-07-08US flag
US9255087No2016-02-092028-07-08US flag
US9029356No2015-05-122028-07-08US flag
US9085565No2015-07-212033-05-22US flag
US8299057No2012-10-302029-03-01US flag
US10398693No2019-09-032038-07-18US flag
US9085558No2015-07-212028-07-08US flag
US10561651No2015-02-192035-02-19US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0089 mg/mLALOGPS
logP5.03ALOGPS
logP5.4ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)12.39ChemAxon
pKa (Strongest Basic)7.78ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area85.52 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity161.24 m3·mol-1ChemAxon
Polarizability60.41 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympatheti...
Gene Name
NTRK1
Uniprot ID
P04629
Uniprot Name
High affinity nerve growth factor receptor
Molecular Weight
87496.465 Da
References
  1. Liu D, Offin M, Harnicar S, Li BT, Drilon A: Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252. doi: 10.2147/TCRM.S147381. eCollection 2018. [PubMed:30050303]
  2. Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, Giallombardo M, Peeters M, Raez L: Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493-500. doi: 10.1517/13543784.2015.1096344. Epub 2015 Oct 12. [PubMed:26457764]
  3. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A: Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016 Apr;15(4):628-39. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. [PubMed:26939704]
  4. Pacenta HL, Macy ME: Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Devel Ther. 2018 Oct 23;12:3549-3561. doi: 10.2147/DDDT.S147384. eCollection 2018. [PubMed:30425456]
  5. FDA Label: Rozlytrek [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein homodimerization activity
Specific Function
Receptor tyrosine kinase involved in the development and the maturation of the central and the peripheral nervous systems through regulation of neuron survival, proliferation, migration, differenti...
Gene Name
NTRK2
Uniprot ID
Q16620
Uniprot Name
BDNF/NT-3 growth factors receptor
Molecular Weight
91998.175 Da
References
  1. Liu D, Offin M, Harnicar S, Li BT, Drilon A: Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252. doi: 10.2147/TCRM.S147381. eCollection 2018. [PubMed:30050303]
  2. Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, Giallombardo M, Peeters M, Raez L: Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493-500. doi: 10.1517/13543784.2015.1096344. Epub 2015 Oct 12. [PubMed:26457764]
  3. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A: Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016 Apr;15(4):628-39. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. [PubMed:26939704]
  4. Pacenta HL, Macy ME: Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Devel Ther. 2018 Oct 23;12:3549-3561. doi: 10.2147/DDDT.S147384. eCollection 2018. [PubMed:30425456]
  5. FDA Label: Rozlytrek [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Receptor tyrosine kinase involved in nervous system and probably heart development. Upon binding of its ligand NTF3/neurotrophin-3, NTRK3 autophosphorylates and activates different signaling pathways, including the phosphatidylinositol 3-kinase/AKT and the MAPK pathways, that control cell survival and differentiation.
Specific Function
Atp binding
Gene Name
NTRK3
Uniprot ID
Q16288
Uniprot Name
NT-3 growth factor receptor
Molecular Weight
94427.47 Da
References
  1. Liu D, Offin M, Harnicar S, Li BT, Drilon A: Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252. doi: 10.2147/TCRM.S147381. eCollection 2018. [PubMed:30050303]
  2. Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, Giallombardo M, Peeters M, Raez L: Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493-500. doi: 10.1517/13543784.2015.1096344. Epub 2015 Oct 12. [PubMed:26457764]
  3. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A: Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016 Apr;15(4):628-39. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. [PubMed:26939704]
  4. Pacenta HL, Macy ME: Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Devel Ther. 2018 Oct 23;12:3549-3561. doi: 10.2147/DDDT.S147384. eCollection 2018. [PubMed:30425456]
  5. FDA Label: Rozlytrek [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Orphan receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2.
Specific Function
Atp binding
Gene Name
ROS1
Uniprot ID
P08922
Uniprot Name
Proto-oncogene tyrosine-protein kinase ROS
Molecular Weight
263912.88 Da
References
  1. Liu D, Offin M, Harnicar S, Li BT, Drilon A: Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252. doi: 10.2147/TCRM.S147381. eCollection 2018. [PubMed:30050303]
  2. Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, Giallombardo M, Peeters M, Raez L: Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493-500. doi: 10.1517/13543784.2015.1096344. Epub 2015 Oct 12. [PubMed:26457764]
  3. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, Ballinari D, Ciomei M, Texido G, Degrassi A, Avanzi N, Amboldi N, Saccardo MB, Casero D, Orsini P, Bandiera T, Mologni L, Anderson D, Wei G, Harris J, Vernier JM, Li G, Felder E, Donati D, Isacchi A, Pesenti E, Magnaghi P, Galvani A: Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications. Mol Cancer Ther. 2016 Apr;15(4):628-39. doi: 10.1158/1535-7163.MCT-15-0758. Epub 2016 Mar 3. [PubMed:26939704]
  4. Pacenta HL, Macy ME: Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. Drug Des Devel Ther. 2018 Oct 23;12:3549-3561. doi: 10.2147/DDDT.S147384. eCollection 2018. [PubMed:30425456]
  5. FDA Label: Rozlytrek [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sh2 domain binding
Specific Function
Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptiv...
Gene Name
JAK2
Uniprot ID
O60674
Uniprot Name
Tyrosine-protein kinase JAK2
Molecular Weight
130672.475 Da
References
  1. FDA Label: Rozlytrek [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Ww domain binding
Specific Function
Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals ...
Gene Name
TNK2
Uniprot ID
Q07912
Uniprot Name
Activated CDC42 kinase 1
Molecular Weight
114567.605 Da
References
  1. FDA Label: Rozlytrek [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. Al-Salama ZT, Keam SJ: Entrectinib: First Global Approval. Drugs. 2019 Aug 1. pii: 10.1007/s40265-019-01177-y. doi: 10.1007/s40265-019-01177-y. [PubMed:31372957]
  2. Liu D, Offin M, Harnicar S, Li BT, Drilon A: Entrectinib: an orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumors. Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252. doi: 10.2147/TCRM.S147381. eCollection 2018. [PubMed:30050303]
  3. FDA Label: Rozlytrek [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Curator comments
The active metabolite M5 is a substrate of P-gp. The parent drug does is an inhibitor of P-gp, but not a substrate.
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

Drug created on October 20, 2016 15:08 / Updated on September 27, 2020 08:17

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