Identification

Name
Duvelisib
Accession Number
DB11952
Type
Small Molecule
Groups
Approved, Investigational
Description

Duvelisib, also known as IPI-145 and INK-1197, is a small-molecule inhibitor of phosphoinositide-3 kinases that was designed initially to prove that simultaneous inhibition of the isoforms delta and gamma can produce a broad adaptative and innate immune cell inhibitory activity. All the work around duvelisib showed that this agent is a potent inhibitor of both forms.[1] Duvelisib was developed by Verastem, Inc and FDA approved on September 24, 2018.[7]

Structure
Thumb
Synonyms
Not Available
External IDs
INK-1147 / INK-1197 / IPI-145
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CopiktraCapsule25 mg/1OralVerastem, Inc.2018-09-25Not applicableUs
CopiktraCapsule15 mg/1OralVerastem, Inc.2018-09-25Not applicableUs
Categories
UNII
610V23S0JI
CAS number
1201438-56-3
Weight
Average: 416.87
Monoisotopic: 416.1152369
Chemical Formula
C22H17ClN6O
InChI Key
SJVQHLPISAIATJ-ZDUSSCGKSA-N
InChI
InChI=1S/C22H17ClN6O/c1-13(28-21-19-20(25-11-24-19)26-12-27-21)17-10-14-6-5-9-16(23)18(14)22(30)29(17)15-7-3-2-4-8-15/h2-13H,1H3,(H2,24,25,26,27,28)/t13-/m0/s1
IUPAC Name
8-chloro-2-phenyl-3-[(1S)-1-[(9H-purin-6-yl)amino]ethyl]-1,2-dihydroisoquinolin-1-one
SMILES
C[C@H](NC1=C2N=CNC2=NC=N1)C1=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1

Pharmacology

Indication

Duvelisib is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies.[8]

The CLL is a cancer of the blood stem cells which are the blood cells that can develop into different types of cells. In leukemia, there is an overproduction of cells that are abnormal and do not mature into blood cells and thus, they just crowd out normal cells and impair their normal function. In lymphocyte leukemia, the abnormal cell growth is observed in the lymphoid cells which are the type of blood cells that mature into lymphocytes. The CLL is the type of lymphocytic leukemia that develops slowly over months or years.[9] The SLL is a very similar disease to the CLL and these terms are usually referred interchangeably. The only difference between these two diseases is that in CLL the cells are found mostly in the blood and bone marrow while in SLL, the cells are mainly found in the lymph nodes.[10]

As well, duvelisib obtained an accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies. This approval is still under the status of continued approval and it is restrained to confirmatory trials.[8]

The follicular lymphoma is a B-cell lymphoma that clusters in the lymph nodes or other tissues.[11]

Associated Conditions
Pharmacodynamics

Preclinical data showed that duvelisib presents cytotoxic actions at micromolar doses and antagonizes the activation of downstream signaling even in the presence of the mutation BTK C481S, which allows for the treatment of patients resistant to ibrutinib.[4]

In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. This trials reported a median progression-free survival of 16.4 months and an overall response rate of 78% which were almost 2-fold what it was reported for ofatumumab.[7]

In clinical trials of follicular lymphoma, duvelisib presented and overall response rate of 42% from which almost all the patients observed a partial response. Of the responding patients, 43% maintained the response for at least 6 months and 17% for at least 12 months.[7]

Mechanism of action

Duvelisib acts as a strong reversible inhibitor of the isoform gamma and delta of the phosphoinositide3-kinase (PI3K).[2] PI3K plays a very important role in innate and adaptative immunity and the inhibition of the form delta and gamma has been very important for the suppression of immunity.[3]

The activity of PI3K gamma and delta is restricted to hematopoietic cells and it is necessary for normal B cell development. In lymphomas, the activation of PI3K is enlarged to promote unlimited growth and survival. Hence, inhibition of PI3K can provide an inhibition of the signaling from BCR, inhibition of a cytokine signaling from the microenvironment and enhancement of anti-tumor immunity.[4] The specific mechanism of this PI3K inhibitors are further described as follows:

-BCR activates signaling pathways after antigen engagement and it is also critical for the physiologic life of the lymphocytes and neoplastic lymphomas. In CLL, BCR reacts to auto- and exo-antigens to promote clonal expansion. This sustained presence of BCR activates delta PI3K producing a pro-survival pathway of the neoplastic cells which already present a higher activity of PI3K. Thus, the blockade of PI3K will limit the activity of BCR and the driven physiology of the lymphoma.[4]

-The inhibition of PI3K can also inhibit paracrine and autocrine pro-survival signals mediated by adhesion molecules, chemokines and soluble factors. This activity is attained due to the fact that several downstream signals convey on PI3K.[5]

-It has been reported that inactivation of PI3K produces a significant resistance to tumorigenesis. This data suggests that inhibition of PI3K can facilitate recognition and elimination of tumor cells.[4]

In summary, duvelisib inhibits the isoform delta of PI3K which is necessary for cell proliferation and survival and the isoform gamma which is critical for cytokine signaling and the pro-inflammatory response.[5]

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

Duvelisib is rapidly absorbed and its peak plasma concentration is reached 1-2 hours after initial administration with a bioavailability of 42% and with a minimal accumulation whose rate ranges between 1.5 and 2.9.[5] The maximal plasma concentration is reported to range in between 471 to 3294 ng/ml with a systemic exposure ranging from 2001 to 19059 ng.h/ml. Changes in the administered dose produce correspondent changes in all absorption parameters indicating a dose-response profile.[6]

Volume of distribution

The volume of distribution of duvelisib ranges from 26 to 102 L.[6]

Protein binding

The protein binding of duvelisib is greater than 98% and this level is not dependent on serum concentration. It is reported that duvelisib is a substrate of P-gp and BCRP.[Label]

Metabolism

Duvelesib is mainly metabolized by CYP3A4.[Label]

Route of elimination

Duvelisib is eliminated after 3.5-9.5 hours when administered as a single dose and after 6.5-11.7 hours when given in multiple doses.[5] From the administered dose, 79% os excreted in feces and 14% in urine. About 10% of the total administered dose is secreted unchanged.[Label]

Half life

The reported half-life of duvelisib is in the range of 5.2 to 10.9 hours.[6]

Clearance

Duvelisib clearance rate is reported to be in the range of 3.6 to 11.2 L/h.[6]

Toxicity

Carcinogenic studies have not been performed and duvelisib did not produce any genetic damage in vitro or in vivo. In the case of fertility studies, there was found some histological abnormalities in male and female rats such as seminiferous epithelial atrophy, decreased testes weight, soft testes, small epididymis, oligo/aspermia, decreased ovary weight, and uterine atrophy.[Label]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Duvelisib can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Duvelisib.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Duvelisib.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Duvelisib.
5-androstenedioneThe metabolism of Duvelisib can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Duvelisib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of Duvelisib can be decreased when combined with 6-O-benzylguanine.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Duvelisib.
AbemaciclibThe serum concentration of Duvelisib can be increased when it is combined with Abemaciclib.
AbirateroneThe metabolism of Duvelisib can be decreased when combined with Abiraterone.
Food Interactions
Not Available

References

General References
  1. Winkler DG, Faia KL, DiNitto JP, Ali JA, White KF, Brophy EE, Pink MM, Proctor JL, Lussier J, Martin CM, Hoyt JG, Tillotson B, Murphy EL, Lim AR, Thomas BD, Macdougall JR, Ren P, Liu Y, Li LS, Jessen KA, Fritz CC, Dunbar JL, Porter JR, Rommel C, Palombella VJ, Changelian PS, Kutok JL: PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013 Nov 21;20(11):1364-74. doi: 10.1016/j.chembiol.2013.09.017. Epub 2013 Nov 7. [PubMed:24211136]
  2. Authors unspecified: IPI-145 shows promise in CLL patients. Cancer Discov. 2014 Feb;4(2):136. doi: 10.1158/2159-8290.CD-NB2013-177. Epub 2013 Dec 12. [PubMed:24501284]
  3. Boyle DL, Kim HR, Topolewski K, Bartok B, Firestein GS: Novel phosphoinositide 3-kinase delta,gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J Pharmacol Exp Ther. 2014 Feb;348(2):271-80. doi: 10.1124/jpet.113.205955. Epub 2013 Nov 15. [PubMed:24244039]
  4. Lampson BL, Brown JR: PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs. 2017 Nov;26(11):1267-1279. doi: 10.1080/13543784.2017.1384815. Epub 2017 Oct 6. [PubMed:28945111]
  5. Vangapandu HV, Jain N, Gandhi V: Duvelisib: a phosphoinositide-3 kinase delta/gamma inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017 May;26(5):625-632. doi: 10.1080/13543784.2017.1312338. Epub 2017 Apr 13. [PubMed:28388280]
  6. Flinn IW, O'Brien S, Kahl B, Patel M, Oki Y, Foss FF, Porcu P, Jones J, Burger JA, Jain N, Kelly VM, Allen K, Douglas M, Sweeney J, Kelly P, Horwitz S: Duvelisib, a novel oral dual inhibitor of PI3K-delta,gamma, is clinically active in advanced hematologic malignancies. Blood. 2018 Feb 22;131(8):877-887. doi: 10.1182/blood-2017-05-786566. Epub 2017 Nov 30. [PubMed:29191916]
  7. FDA news [Link]
  8. MarketWatch [Link]
  9. Canadian Cancer Society [Link]
  10. Cancer.gov [Link]
  11. Canadian Cancer Society [Link]
External Links
KEGG Drug
D10555
PubChem Compound
50905713
PubChem Substance
347828278
ChemSpider
28637766
ChEBI
131169
ChEMBL
CHEMBL3039502
Wikipedia
Duvelisib
FDA label
Download (307 KB)
MSDS
Download (13.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers5
1CompletedBasic ScienceHepatic Impairment1
1CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / Malignant Lymphomas / Non-Hodgkin's Lymphoma (NHL) / T-Cell Lymphomas1
1CompletedTreatmentMalignant Lymphomas1
1RecruitingTreatmentMalignant Lymphomas / Relapsed/Refractory T-cell Lymphomas1
1TerminatedTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
1TerminatedTreatmentMalignancies, Hematologic1
1WithdrawnTreatmentChronic Lymphocytic Leukaemia (CLL) / Non-Hodgkin's Lymphoma (NHL) / Small Lymphocytic Lymphoma (SLL)1
1, 2Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)1
1, 2CompletedTreatmentCD20+ Follicular Lymphoma1
1, 2RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL)1
2Active Not RecruitingTreatmentIndolent Non-Hodgkin's Lymphomas1
2Active Not RecruitingTreatmentMalignancies, Hematologic1
2CompletedTreatmentRheumatoid Arthritis1
2RecruitingTreatmentPeripheral T-Cell Lymphoma (PTCL)1
2SuspendedTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
2WithdrawnTreatmentLeukemias1
2WithdrawnTreatmentMalignant Lymphomas1
3Active Not RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
3Enrolling by InvitationTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
3TerminatedTreatmentFollicular Lymphoma (FL)1
3WithdrawnTreatmentFollicular Lymphoma (FL) / Indolent Non-Hodgkin's Lymphomas / Marginal Zone Lymphoma / Small Lymphocytic Lymphoma (SLL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral15 mg/1
CapsuleOral25 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>190 ºC'MSDS'
water solubility<1 mg/ml'MSDS'
logP4.55'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.0195 mg/mLALOGPS
logP3.91ALOGPS
logP3.67ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)9.86ChemAxon
pKa (Strongest Basic)3.99ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area86.8 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity118.53 m3·mol-1ChemAxon
Polarizability42.2 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 isoquinolones and derivatives. These are aromatic polycyclic compounds containing a ketone bearing isoquinoline moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Isoquinolines and derivatives
Sub Class
Isoquinolones and derivatives
Direct Parent
Isoquinolones and derivatives
Alternative Parents
6-alkylaminopurines / Secondary alkylarylamines / Pyridinones / Aminopyrimidines and derivatives / Aryl chlorides / Benzene and substituted derivatives / Imidolactams / Vinylogous halides / Imidazoles / Heteroaromatic compounds
show 7 more
Substituents
Isoquinolone / 6-alkylaminopurine / 6-aminopurine / Imidazopyrimidine / Purine / Aminopyrimidine / Pyridinone / Secondary aliphatic/aromatic amine / Aryl chloride / Aryl halide
show 23 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(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recr...
Gene Name
PIK3CG
Uniprot ID
P48736
Uniprot Name
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Molecular Weight
126452.625 Da
References
  1. Boyle DL, Kim HR, Topolewski K, Bartok B, Firestein GS: Novel phosphoinositide 3-kinase delta,gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J Pharmacol Exp Ther. 2014 Feb;348(2):271-80. doi: 10.1124/jpet.113.205955. Epub 2013 Nov 15. [PubMed:24244039]
  2. Lampson BL, Brown JR: PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs. 2017 Nov;26(11):1267-1279. doi: 10.1080/13543784.2017.1384815. Epub 2017 Oct 6. [PubMed:28945111]
  3. Vangapandu HV, Jain N, Gandhi V: Duvelisib: a phosphoinositide-3 kinase delta/gamma inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017 May;26(5):625-632. doi: 10.1080/13543784.2017.1312338. Epub 2017 Apr 13. [PubMed:28388280]
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
References
  1. Boyle DL, Kim HR, Topolewski K, Bartok B, Firestein GS: Novel phosphoinositide 3-kinase delta,gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis. J Pharmacol Exp Ther. 2014 Feb;348(2):271-80. doi: 10.1124/jpet.113.205955. Epub 2013 Nov 15. [PubMed:24244039]
  2. Lampson BL, Brown JR: PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma. Expert Opin Investig Drugs. 2017 Nov;26(11):1267-1279. doi: 10.1080/13543784.2017.1384815. Epub 2017 Oct 6. [PubMed:28945111]
  3. Vangapandu HV, Jain N, Gandhi V: Duvelisib: a phosphoinositide-3 kinase delta/gamma inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017 May;26(5):625-632. doi: 10.1080/13543784.2017.1312338. Epub 2017 Apr 13. [PubMed:28388280]

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

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
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
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

Drug created on October 20, 2016 15:04 / Updated on November 02, 2018 07:17