Identification

Name
Copanlisib
Accession Number
DB12483
Type
Small Molecule
Groups
Approved, Investigational
Description

Copanlisib is a selective pan-Class I phosphoinositide 3-kinase (PI3K/Phosphatidylinositol-4,5-bisphosphate 3-kinase/phosphatidylinositide 3-kinase) inhibitor that was first developed by Bayer Healthcare Pharmaceuticals, Inc. The drug targets the enzyme that plays a role in regulating cell growth and survival. Copanlisib was granted accelerated approval on September 14, 2017 under the market name Aliqopa for the treatment of adult patients with relapsed follicular lymphoma and a treatment history of at least two prior systemic therapies. Follicular lymphoma is a slow-growing type of non-Hodgkin lymphoma that is caused by unregulated proliferation and growth of lymphocytes. The active ingredient in Aliquopa intravenous therapy is copanlisib dihydrochloride.

Structure
Thumb
Synonyms
Not Available
External IDs
BAY-80-6946 / BAY80-6946
Product Ingredients
IngredientUNIICASInChI Key
Copanlisib dihydrochloride03ZI7RZ52O1402152-13-9STGQPVQAAFJJFX-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AliqopaInjection, powder, lyophilized, for solution15 mg/1mLIntravenousBayer HealthCare Pharmaceuticals Inc.2017-09-14Not applicableUs
Categories
UNII
WI6V529FZ9
CAS number
1032568-63-0
Weight
Average: 480.529
Monoisotopic: 480.223351414
Chemical Formula
C23H28N8O4
InChI Key
PZBCKZWLPGJMAO-UHFFFAOYSA-N
InChI
InChI=1S/C23H28N8O4/c1-33-19-17(35-10-2-6-30-8-11-34-12-9-30)4-3-16-18(19)28-23(31-7-5-25-20(16)31)29-21(32)15-13-26-22(24)27-14-15/h3-4,13-14H,2,5-12H2,1H3,(H2,24,26,27)(H,28,29,32)
IUPAC Name
2-amino-N-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2H,3H-imidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide
SMILES
COC1=C(OCCCN2CCOCC2)C=CC2=C1N=C(NC(=O)C1=CN=C(N)N=C1)N1CCN=C21

Pharmacology

Indication

Indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

Associated Conditions
Pharmacodynamics

Copanlisib has demonstrated potent anti-tumor and pro-apoptotic activity in various tumor cell lines and xenograft models [1]. In clinical trials, 59 percent of patients receiving copanlisib achieved complete or partial shrinkage of their tumors after a median of 12.2 months [2]. Higher systemic levels of copanlisib is associated with elevated plasma glucose levels.

Mechanism of action

Follicular lymphoma is a B-cell lymphoma that is one of the most common type of non-Hodgkin lymphoma (NHL). It involves unregulated growth and proliferation of lymphocytes that eventually may travel to other organs including the lymph nodes, spleen, and the bone marrow, to form tumors. The phosphatidylinositol 3-kinase (PI3K)-mediated pathway is involved in promoting cell survival proliferation and differentiation however abberant activation of this pathway may lead to tumorigenesis [1]. Copanlisib mediates an inhibitory action on p110α and p110δ isoforms of phosphatidylinositol-3-kinase (PI3K) expressed in malignant B cells. It induces tumor cell death via apoptosis and inhibits the proliferation of primary malignant B cell lines [Label]. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines [Label].

TargetActionsOrganism
APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
inhibitor
Human
APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
inhibitor
Human
Absorption

The plasma levels of copanlisib increases in a dose-proportional manner with linear pharmacokinetic properties and no time dependency. Following a steady state exposure at 0.8 mg/kg, the mean peak plasma concentration (Cmax) of copanlisib is 463 ng/mL with the range of 105 to 1670 ng/mL [Label].

Volume of distribution

The in vitro mean blood-to-plasma ratio is 1.7 (range: 1.5 to 2.1). The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L.

Protein binding

The in vitro human plasma protein binding of copanlisib is 84.2%, with albumin being the main binding protein [Label].

Metabolism

Approximately >90% of copanlisib metabolism is mediated by CYP3A and less than 10% of the drug is metabolized by CYP1A1. The main detectable metabolite is M-1 that retains a comparable pharamcological activity to the parent drug against PI3Kα and PI3Kβ [Label].

Route of elimination

Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. After a single intravenously-administered dose of 12mg radiolableled drug, approximately 64% of the dose is excreted in feces and 22% is excreted in urine within 20 to 34 days. Unchanged copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation metabolism accounted for 41% of the administered dose [Label].

Half life

The geometric mean terminal elimination half-life of copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours [Label].

Clearance

The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr [Label].

Toxicity

Copanlisib is not shown to exhibit mutagenetic actions in vitro or in vivo. In the repeat dose toxicity studies, copanlisib led to adverse events in the reproductive systems of male and female rats. The effects on male rats included adverse events on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Copanlisib induced adverse events on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus [Label].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenThe serum concentration of Copanlisib can be increased when it is combined with Acetaminophen.
Acetyl sulfisoxazoleThe metabolism of Copanlisib can be decreased when combined with Acetyl sulfisoxazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Copanlisib.
AlfuzosinThe metabolism of Copanlisib can be decreased when combined with Alfuzosin.
AmcinonideThe metabolism of Amcinonide can be decreased when combined with Copanlisib.
AmiodaroneThe serum concentration of Copanlisib can be increased when it is combined with Amiodarone.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Copanlisib.
AmlodipineThe serum concentration of Copanlisib can be increased when it is combined with Amlodipine.
AmsacrineThe serum concentration of Copanlisib can be increased when it is combined with Amsacrine.
ApalutamideThe serum concentration of Copanlisib can be decreased when it is combined with Apalutamide.
Food Interactions
Not Available

References

General References
  1. Patnaik A, Appleman LJ, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Weiss GJ, Sachdev JC, Chadha M, Fulk M, Ejadi S, Mountz JM, Lotze MT, Toledo FG, Chu E, Jeffers M, Pena C, Xia C, Reif S, Genvresse I, Ramanathan RK: First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas. Ann Oncol. 2016 Oct;27(10):1928-40. doi: 10.1093/annonc/mdw282. [PubMed:27672108]
  2. FDA Press Announcements: FDA approves new treatment for adults with relapsed follicular lymphoma [Link]
External Links
PubChem Compound
24989044
PubChem Substance
347828721
ChemSpider
25069683
ChEMBL
CHEMBL3218576
HET
6E2
Wikipedia
Copanlisib
PDB Entries
5g2n
FDA label
Download (288 KB)
MSDS
Download (27.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherOncology, Medical1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedOtherNon Hodgkin Lymphoma (NHL)1
1CompletedTreatmentNeoplasms5
1Not Yet RecruitingTreatmentDeleterious BRCA1 Gene Mutation / Deleterious BRCA2 Gene Mutation / Endometrial Adenocarcinomas / High Grade Ovarian Serous Adenocarcinoma / Primary Peritoneal High Grade Serous Adenocarcinoma / Recurrent Endometrial Carcinoma / Recurrent Fallopian Tube Carcinoma / Recurrent Ovarian Carcinoma / Recurrent Primary Peritoneal Carcinoma1
1Not Yet RecruitingTreatmentHealthy Volunteers1
1RecruitingBasic ScienceNeoplasms Malignant / Non-Hodgkin's Lymphoma (NHL)1
1RecruitingTreatmentAdvanced or Metastatic Solid Tumor1
1RecruitingTreatmentAnn Arbor Stage III Lymphoma / Ann Arbor Stage IV Lymphoma / Metastatic Malignant Solid Neoplasm1
1RecruitingTreatmentHER2 Positive Breast Cancers1
1, 2Active Not RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
1, 2RecruitingTreatmentCarcinoma, Squamous Cell of Head and Neck1
1, 2RecruitingTreatmentEstrogen Receptor Positive / HER2/Neu Negative / Invasive Breast Carcinoma / Multifocal Breast Carcinoma / One to five years postmenopausal / Progesterone Receptor Positive / Stage I Breast Carcinoma / Stage IA Breast Cancer / Stage IB Breast Cancer / Stage II Breast Cancer / Stage IIA Breast Cancer / Stage IIB Breast Cancer / Stage III Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
1, 2RecruitingTreatmentMature T-Cell and NK-Cell Neoplasm1
1, 2RecruitingTreatmentRefractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL)1
2Active Not RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
2CompletedTreatmentLymphoma, Diffuse Large-Cell / Lymphoma, Large B-Cell, Diffuse (DLBCL)1
2Not Yet RecruitingTreatmentMarginal Zone Lymphoma1
2Not Yet RecruitingTreatmentRecurrent Diffuse Large B-Cell Lymphoma / Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma / Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma / Refractory Diffuse Large B Cell Lymphoma / Refractory Mediastinal (Thymic) Large B-Cell Cell Lymphoma / Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma1
2RecruitingTreatmentBiliary Carcinoma / Cholangiocarcinomas / Gall Bladder Carcinoma / Gastrointestinal Tumors1
2SuspendedTreatmentEndometrial Endometrioid Adenocarcinoma / Endometrial Mixed Adenocarcinoma / Endometrial Serous Adenocarcinoma / Endometrial Undifferentiated Carcinoma / Metastatic Endometrioid Adenocarcinoma / PIK3CA Gene Mutation / Recurrent Uterine Corpus Carcinoma1
2TerminatedTreatmentMantle Cell Lymphoma (MCL)1
2WithdrawnTreatmentEstrogen Receptor Positive / HER2/Neu Negative / Progesterone Receptor Positive / Stage IV Breast Cancer AJCC v6 and v71
3Active Not RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1
3RecruitingTreatmentLymphoma,Non-Hodgkin1
3RecruitingTreatmentNon-Hodgkin's Lymphoma (NHL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous15 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9636344No2012-03-292032-03-29Us
US8466283No2009-10-222029-10-22Us
US7511041No2004-05-132024-05-13Us
USRE46856No2009-10-222029-10-22Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.231 mg/mLALOGPS
logP1.02ALOGPS
logP0.32ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)10.15ChemAxon
pKa (Strongest Basic)6.88ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area139.79 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity132.78 m3·mol-1ChemAxon
Polarizability51.76 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolinamines
Alternative Parents
Pyrimidinecarboxamides / Anisoles / Alkyl aryl ethers / Aminopyrimidines and derivatives / Morpholines / Imidolactams / Imidazolines / Heteroaromatic compounds / Trialkylamines / Amino acids and derivatives
show 10 more
Substituents
Quinazolinamine / Pyrimidinecarboxamide / Pyrimidine-5-carboxylic acid or derivatives / Anisole / Phenol ether / Alkyl aryl ether / Aminopyrimidine / Pyrimidine / Imidolactam / Morpholine
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein serine/threonine kinase activity
Specific Function
Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate...
Gene Name
PIK3CA
Uniprot ID
P42336
Uniprot Name
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Molecular Weight
124283.025 Da
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Specific Function
Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by rec...
Gene Name
PIK3CD
Uniprot ID
O00329
Uniprot Name
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Molecular Weight
119478.065 Da

Enzymes

Kind
Protein
Organism
Human
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
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
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
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
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
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Monooxygenase activity
Specific Function
Exhibits low testosterone 6-beta-hydroxylase activity.
Gene Name
CYP3A43
Uniprot ID
Q9HB55
Uniprot Name
Cytochrome P450 3A43
Molecular Weight
57669.21 Da

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
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

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
IC50: 0.09 uM
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da

Drug created on October 20, 2016 16:33 / Updated on September 21, 2018 00:19