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
Structure for Duvelisib (DB11952)
- Synonyms
- Not Available
- External IDs
- INK-1147 / INK-1197 / IPI-145
- 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]
Target Actions Organism APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform inhibitorHuman APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform inhibitorHuman - 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
Drug Interaction (4R)-limonene The risk or severity of adverse effects can be increased when (4R)-limonene is combined with Duvelisib. 16-Bromoepiandrosterone The risk or severity of adverse effects can be increased when Duvelisib is combined with 16-Bromoepiandrosterone. 19-norandrostenedione The risk or severity of adverse effects can be increased when Duvelisib is combined with 19-norandrostenedione. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be decreased when combined with Duvelisib. 5-androstenedione The risk or severity of adverse effects can be increased when Duvelisib is combined with 5-androstenedione. 6-Deoxyerythronolide B The metabolism of Duvelisib can be decreased when combined with 6-Deoxyerythronolide B. Abemaciclib Abemaciclib may decrease the excretion rate of Duvelisib which could result in a higher serum level. Acalabrutinib The metabolism of Duvelisib can be decreased when combined with Acalabrutinib. Aceclofenac The risk or severity of adverse effects can be increased when Duvelisib is combined with Aceclofenac. Acemetacin The risk or severity of adverse effects can be increased when Duvelisib is combined with Acemetacin. - Food Interactions
- Not Available
References
- General References
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- FDA news [Link]
- MarketWatch [Link]
- Canadian Cancer Society [Link]
- Cancer.gov [Link]
- Canadian Cancer Society [Link]
- External Links
- FDA label
- Download (307 KB)
- MSDS
- Download (13.2 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) >190 ºC 'MSDS' water solubility <1 mg/ml 'MSDS' logP 4.55 'MSDS' - Predicted Properties
Property Value Source Water Solubility 0.0195 mg/mL ALOGPS logP 3.91 ALOGPS logP 3.67 ChemAxon logS -4.3 ALOGPS pKa (Strongest Acidic) 9.86 ChemAxon pKa (Strongest Basic) 3.99 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 5 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 86.8 Å2 ChemAxon Rotatable Bond Count 4 ChemAxon Refractivity 118.53 m3·mol-1 ChemAxon Polarizability 42.2 Å3 ChemAxon Number of Rings 5 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not 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
- 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]
- 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]
- 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
- 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]
- 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]
- 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 October 20, 2018 09:38