Duvelisib

Identification

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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

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Duvelisib (DB11952)

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Synonyms

• Duvelisib

External IDs

INK-1147 / INK-1197 / IPI-145

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
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Copiktra	Capsule	15 mg/1	Oral	Verastem, Inc.	2018-09-25	Not applicable
Copiktra	Capsule	25 mg/1	Oral	Verastem, Inc.	2018-09-25	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Categories

• BCRP/ABCG2 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates (strength unknown)
• Heterocyclic Compounds, Fused-Ring
• P-glycoprotein/ABCB1 Substrates
• Phosphatidylinositol 3-Kinases, antagonists & inhibitors

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

• Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
• Relapsed or Refractory Follicular Lymphoma
• Refractory, relapsed small lymphocytic lymphoma

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	inhibitor	Humans
APhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	inhibitor	Humans

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Adverse Effects

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Contraindications

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Blackbox Warnings

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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

• All Drugs
• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental

Drug	Interaction
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(R)-warfarin	The metabolism of Duvelisib can be decreased when combined with (R)-warfarin.
(S)-Warfarin	The metabolism of (S)-Warfarin can be decreased when combined with Duvelisib.
3,5-diiodothyropropionic acid	The metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Duvelisib.
4-hydroxycoumarin	The metabolism of 4-hydroxycoumarin can be decreased when combined with Duvelisib.
5-androstenedione	The metabolism of Duvelisib can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide B	The metabolism of Duvelisib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanine	The metabolism of Duvelisib can be decreased when combined with 6-O-benzylguanine.
7-ethyl-10-hydroxycamptothecin	The metabolism of Duvelisib can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-aminocamptothecin	The metabolism of 9-aminocamptothecin can be decreased when combined with Duvelisib.
Abatacept	The metabolism of Duvelisib can be increased when combined with Abatacept.

Additional Data Available

Extended Description
Extended Description
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Severity
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Evidence Level
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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

BindingDB

50193013

ChEBI

131169

ChEMBL

CHEMBL3039502

Wikipedia

Duvelisib

FDA label

Download (307 KB)

MSDS

Download (13.2 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
1	Completed	Basic Science	Healthy Volunteers	5
1	Completed	Basic Science	Hepatic Impairment	1
1	Completed	Treatment	Chronic Lymphocytic Leukaemia (CLL) / Malignant Lymphomas / Non-Hodgkin's Lymphoma (NHL) / T-Cell Lymphomas	1
1	Completed	Treatment	Malignant Lymphomas	1
1	Not Yet Recruiting	Treatment	Chronic Lymphocytic Leukaemia (CLL) / Recurrent Diffuse Large B-Cell Lymphoma / Refractory Diffuse Large B Cell Lymphoma / Richter's Syndrome / Small Lymphocytic Lymphoma (SLL) / Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma / Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma / Transformed Small Lymphocytic Lymphoma to Diffuse Large B-Cell Lymphoma	1
1	Recruiting	Treatment	Malignant Lymphomas / Relapsed/Refractory T-cell Lymphomas	1
1	Terminated	Treatment	Chronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)	1
1	Terminated	Treatment	Malignancies, Hematologic	1
1	Withdrawn	Treatment	Chronic Lymphocytic Leukaemia (CLL) / Non-Hodgkin's Lymphoma (NHL) / Small Lymphocytic Lymphoma (SLL)	1
1, 2	Active Not Recruiting	Treatment	Chronic Lymphocytic Leukaemia (CLL)	1
1, 2	Recruiting	Treatment	Chronic Lymphocytic Leukaemia (CLL)	1
1, 2	Terminated	Treatment	CD20+ Follicular Lymphoma	1
2	Active Not Recruiting	Treatment	Indolent Non-Hodgkin's Lymphomas	1
2	Active Not Recruiting	Treatment	Malignancies, Hematologic	1
2	Completed	Treatment	Rheumatoid Arthritis	1
2	Not Yet Recruiting	Treatment	Chronic Lymphocytic Leukemia (CLL) - Refractory / Chronic, recurrent Lymphocytic Leukemia / Recurrent Small Lymphocytic Lymphoma / Refractory Small Lymphocytic Lymphoma	1
2	Recruiting	Treatment	Peripheral T-Cell Lymphoma (PTCL)	1
2	Suspended	Treatment	Chronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)	1
2	Withdrawn	Treatment	Leukemias	1
2	Withdrawn	Treatment	Malignant Lymphomas	1
3	Active Not Recruiting	Treatment	Chronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)	1
3	Enrolling by Invitation	Treatment	Chronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)	1
3	Terminated	Treatment	Follicular Lymphoma (FL)	1
3	Withdrawn	Treatment	Follicular Lymphoma (FL) / Indolent Non-Hodgkin's Lymphomas / Marginal Zone Lymphoma / Small Lymphocytic Lymphoma (SLL)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage forms

Form	Route	Strength
Capsule	Oral	15 mg/1
Capsule	Oral	25 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
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US9216982	No	2015-12-22	2029-01-05
US9840505	No	2017-12-12	2032-01-10
US8193182	No	2012-06-05	2030-02-13
USRE46621	No	2017-12-05	2032-05-17

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
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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 compoundsLactams / Azacyclic compounds / Hydrocarbon derivatives / Organopnictogen compounds / Organic oxides / Organochlorides / Organooxygen compounds

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Substituents

Isoquinolone / 6-alkylaminopurine / 6-aminopurine / Imidazopyrimidine / Purine / Aminopyrimidine / Pyridinone / Secondary aliphatic/aromatic amine / Aryl chloride / Aryl halideMonocyclic benzene moiety / Pyridine / Pyrimidine / Benzenoid / Imidolactam / Azole / Vinylogous halide / Heteroaromatic compound / Imidazole / Lactam / Secondary amine / Azacycle / Amine / Organic oxide / Organopnictogen compound / Organohalogen compound / Organic oxygen compound / Organochloride / Organic nitrogen compound / Organonitrogen compound / Organooxygen compound / Hydrocarbon derivative / Aromatic heteropolycyclic compound

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Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

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Drug created on October 20, 2016 15:04 / Updated on July 13, 2019 00:58