Deregulation of hepatic mek1/2–erk1/2 signaling module in iron overload conditions

Article abstract of DOI:10.3390/ph12020069

The liver, through the production of iron hormone hepcidin, controls body iron levels. High liver iron levels and deregulated hepcidin expression are commonly observed in many liver diseases including highly prevalent genetic iron overload disorders. In spite of a number of breakthrough investigations into the signals that control hepcidin expression, little progress has been made towards investigations into intracellular signaling in the liver under excess of iron. This study examined hepatic signaling pathways underlying acquired and genetic iron overload conditions. Our data? demonstrate that hepatic iron overload associates with a decline in the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) kinase (Mek1/2) pathway by selectively affecting the phosphorylation of Erk1/2. We propose that Mek1/2-Erk1/2 signaling is uncoupled from iron-Bmp-Smad-mediated hepcidin induction and that it may contribute to a number of liver pathologies in addition to toxic effects of iron. We believe that our findings will advance the understanding of cellular signaling events in the liver during iron overload of different etiologies.

Full text of DOI:10.3390/ph12020069

pharmaceuticals
Brief Report
Duvelisib: A 2018 Novel FDA-Approved Small
Molecule Inhibiting Phosphoinositide 3-Kinases
Daniel A. Rodrigues 1,2 , Fernanda S. Sagrillo 1 and Carlos A. M. Fraga 1,2,
*
1
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas,
Universidade Federal do Rio de Janeiro, PO Box 68023, Rio de Janeiro, RJ 21941-902, Brazil;
dar.go.qfm@gmail.com (D.A.R.); fefa_uff@yahoo.com.br (F.S.S.)
2
Programa de Pós-Graduação em Química, Instituto de Química, Universidade Federal do Rio de Janeiro,
Rio de Janeiro, RJ 21941-909, Brazil
*
Correspondence: cmfraga@ccsdecania.ufrj.br; Tel.: +55-21-39386447
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 10 April 2019; Accepted: 4 May 2019; Published: 6 May 2019
Abstract: Duvelisib (Copiktra®) is a dual inhibitor of phosphoinositide 3-kinases (PI3K
δ and PI3Kγ).
In 2018, duvelisib was first approved by the Food and Drug Administration (FDA) for the treatment
of adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL)/ small lymphocytic
lymphoma (SLL) after at least two prior therapies. Duvelisib has also been approved under accelerated
track for relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies.
In this review, we provide a series of information about duvelisib, such as the development of clinical
trials for LLC/SLL and FL and the steps used for its synthesis.
Keywords: approved drugs; duvelisib; Copiktra; FDA; phosphoinositide 3-kinases; cancer
1. Introduction
In 2014, Food and Drug Administration (FDA) approved the idelalisib (
of PI3K , for the treatment of relapsed chronic lymphocytic leukaemia (CLL), relapsed follicular B-cell
non-Hodgkin lymphoma (NHL) and relapsed small lymphocytic leukaemia (SLL) [ ]. Although idelalisib
) (Figure 1) possesses an enhanced selectivity for the PI3K , it opened a new road ahead for the family
of phosphoinositide 3-kinase (PI3K) inhibitors. In 2017, the approval of copanlisib ( ) (Figure 1) for the
1), a first-in-class inhibitor
δ
1
(1
δ
2
treatment of relapsed follicular lymphoma (FL) and the ongoing trials on several hematological and solid
malignancies has showed the usefulness of the pan-PI3K inhibitors in the clinics [2,3].
Figure 1. Chemical structure of PI3K inhibitor drugs idelalisib (1) and copanlisib (2).
The purpose of this review is to provide a series of information on the third PI3K inhibitor
approved by FDA in 2018: duvelisib (IPI-145, formerly developed by Intellikine and further developed
by Infinity Pharmaceuticals, which granted to Verastem Oncology in 2016 the rights of development
and commercialization worldwide [4]).
Pharmaceuticals 2019, 12, 69; doi:10.3390/ph12020069
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2. Duvelisib
2.1. Names and Structure
Duvelisib (3
, Figure 2) is commercialized by Verastem Oncology, under the brand name Copiktra®.
Its IUPAC name is: (S)-3-(1-((7H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one,
CAS 1201438-56-3.
Figure 2. Chemical structure of duvelisib (3).
2.2. Uses
Duvelisib (
3) was first approved on September 24, 2018, in the USA, for the treatment of adult
patients with relapsed or refractory CLL/ SLL after at least two prior therapies (NCT02004522) [5,6
].
Based on overall response rate (ORR) the drug has also been approved under fast track for the treatment
of relapsed or refractory FL after at least two prior systemic therapies, but the continued approval
depends on the clinical benefit demonstrated in the trials (NCT02204982) [7].
2.3. Targets and Selectivity
The phosphoinositide 3-kinases (PI3Ks) play an important role in various processes, such as
proliferation, differentiation, motility, survival, and intracellular trafficking [
8–11]. This signaling
pathway is commonly activated in cancer [10]. There are three classes of PI3K, but the drug discovery
process is mainly focused in the enzymes of class I, which is divided into class IA (PI3Kα, PI3Kβ and
PI3Kδ) and IB (PI3Kγ) [12].
Duvelisib (
over PI3K (Table 1). The selectivity for PI3K
the compounds adopt in the active site, namely propeller-shaped, which opens a hydrophobic pocket
that is not present in the apoenzyme [13 14]. Duvelisib ( ) was shown to be selective for the inhibition
of PI3K from class I, not being active against other protein or lipid kinases [15].
3
) is a dual PI3K
δ
and PI3K
γ
inhibitor with enhanced selectivity for PI3K
δ (10-fold)
γ
δ
over PI3K can be attributed to the conformation that
α
,
3
Table 1. Inhibitory profile of idelalisib (
1), copanlisib (2), and duvelisib (3) against each PI3K isoform
(IC50 values in nM).
Drug
PI3Kα
PI3Kβ
PI3Kδ
PI3Kγ
Reference
Idelalisib (1)
Copanlisib (2)
Duvelisib (3)
8600
0.5
1602
4000
3.7
85
19
6.4
2.5
2100
0.7
27
[13]
[3]
[15]
Although there is no crystal structure of the duvelisib (
3) in the active site of PI3K, this drug
should possess a similar interaction mode of idelalisib ( ), given the structural similarities between
1
these two compounds. Figure 3 presents the binding modes of idelalisib (1) in PI3Kδ (PDB:4XE0) [13]
and copanlisib (2) in PI3Kγ (PDB:5G2N) [3].

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Figure 3. Binding modes of idelalisib (1) in PI3Kδ (PDB:4XE0) (A) and copanlisib (2) in PI3Kγ
(PDB:5G2N) (B).
The duvelisib (
the PI3K family [ 16
protein kinase inhibitors, incorporating features related to the inhibition of PI3K [18
3
, ,
) binds at the ATP binding region, which is one of the most conserved throughout
17]. It is possible to explore the model generally used for the development of
19]. In general,
8
,
PI3K inhibitors form hydrogen bond interactions in the region of the hinge, occupying the adenine
binding site (Figure 4). The presence of the hydrophobic regions I and II in the active site of PI3K should
be noted [20]. The former is also called the “affinity pocket” and it is commonly exploited by pan-PI3K
inhibitors through a series of polar interactions. On the other hand, the hydrophobic region II is
a region exposed to the solvent [20]. The compounds with the so-called propeller-shaped conformation
open a hydrophobic pocket between the residues of tryptophan and methionine, also known as the
“specificity pocket”, conferring selectivity for PI3Kδ [20] (Figure 4).
Figure 4. General model for the design of PI3K inhibitors [18,19].
Although the duvelisib (
3
) presents a high similarity to idelalisib (
1), it possesses unique features
related with to the binding affinity by PI3K. Duvelisib (
3) presents a long target residence time,
which may be closely associated with more durable effects [15].
2.4. Clinical Trials
The differential profile of the duvelisib (3) is based on the dual inhibition of PI3K
δ and PI3Kγ,
which are mainly expressed in the immune system [10
,
21]. They present a non-overlapping cellular

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function in the immune system, considering the innate and adaptive immune response [22–24].
Several clinical trials with duvelisib (3) are completed and ongoing for the treatment of cancer,
inflammatory, and autoimmune diseases.
During the phase I studies, assessment of the maximum tolerated dose (MTD), after dosing range
up to 100 mg twice daily, showed that the MTD was 75 mg twice daily based on dose-limiting toxicities
(DLT) [25]. The pharmacodynamics evaluation by inhibition of p-AKT showed that inhibition of this
mediator was not dose-dependent; it was maximal when duvelisib (
daily. The use of duvelisib administered 25 mg twice daily advanced for the phase II and III studies [25].
Following administration of the duvelisib ( ), the phosphorylated-AKT (p-AKT) levels were decreased.
The p-AKT is a downstream marker of PI3K/AKT/mTOR pathway signaling. It is important to note
that the administration of the duvelisib ( ) leads to reduced levels of some chemokines, cytokines,
and matrix metalloproteinases [25 27]. The reduction of several serum factors is consistent with
alterations in the tumor microenvironment [25–27].
Duvelisib ( ) is rapidly absorbed, with a maximum concentration after 1–3 h [25]. Following the
administration of 25 mg of duvelisib ( ), the absolute bioavailability in healthy volunteers is 42% [28].
Duvelisib ( ) presents a volume of distribution of 28.5 L which is consistent with distribution to
peripheral tissues. It is eliminated with a half-life of 4.7 h [28]. Duvelisib ( ) is primarily metabolized
3) was administered 25 mg twice
3
3
–
3
3
3
3
by cytochrome P450 CYP3A4. The concomitant use with a strong inhibitor of CYP3A4 can increase the
risk of toxic effects [4,28].
As expected, the most common adverse events in pretreated patients were the occurrence of
opportunistic infections and cytopenias, with some cases resulting in fatal events [25
) showed clinical efficacy and acceptable safety for the treatment of heavily pretreated patients with
hematological malignancies, showing an overall response rate (ORR) higher than 50% [25–27,29].
In the phase III study for the relapsed or refractory CLL/SLL (NCT02004522) [ ], the efficacy
and safety of duvelisib ( ) was compared with ofatumumab, an approved monoclonal antibody.
Duvelisib ( ) monotherapy showed a significant improvement of the ORR when compared with
–27,29]. Duvelisib
(3
6
3
3
ofatumumab, resulting in the approval of this drug as an additional option for treatment of relapsed or
refractory CLL/SLL [5].
Combinations of the duvelisib (
treatment of cancer. Duvelisib ( ) is being tested in combination with romidepsin or bortezomib against
relapsed/refractory T-cell lymphomas (NCT02783625) [30]. Duvelisib ( ) is also being combined with
3) with other approved drugs are under clinical studies for the
3
3
venetoclax for the treatment of relapsed or refractory CLL or SLL (NCT03534323) [31].
The clinical trials for the treatment of inflammatory and autoimmune diseases were both phase
II studies, where the safety and efficacy of duvelisib (3) was tested for the treatment of asthma
(NCT01653756) [32] and moderate to severe rheumatoid arthritis (NCT01851707) [33], respectively.
2.5. Syntheses
Duvelisib (3) can be obtained by two synthetic routes [34,35]. These routes differ in preparing the
key intermediate, tert-butyl (S)-4-(3-chloro-2-(phenylcarbamoyl)phenyl)-3-oxobutan-2-ylcarbamate
(10), from two different methods (Scheme 1).
In method A, the (S)-2-aminopropanoic acid (
methanol to form (S)-methyl 2-aminopropanoate hydrochloride (
protected by its reaction with di-tert-butyl dicarbonate. The protected intermediate
coupled with the carbanion derived from 2-chloro-6-methyl-N-phenylbenzamide ( ), giving the key
intermediate 10. In method B, N,O-dimethylhydroxylamine hydrochloride was added to a mixture of
(S)-2-(tert-butoxycarbonylamino)propanoic acid , triethylamine, HOBt, EDCI in dichloromethane for
4
) reacted with thionyl chloride and anhydrous
). The amine group on was
was then
5
5
6
9
7
the preparation of (S)-tert-butyl-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (
reaction with the carbanion of 9, furnished the same key intermediate 10.
8), which, after

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Scheme 1. Methods for preparing the key intermediary, tert-butyl (S)-4-(3-chloro-2-(phenylcarbamoyl)phenyl)-
3-oxobutan-2-ylcarbamate (10).
Treatment of the key intermediate 10 with hydrochloric acid in MeOH resulted in deprotection of
the amine group and cyclization to form the isoquinolinone derivative 11 (Scheme 2). Next, the aromatic
nucleophilic substitution reaction between 11 and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (12) was
carried out, yielding 8-chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)
isoquinolin-1(2H)-one (13). Finally, compound 13 was treated with hydrochloric acid in ethanol to remove
the THP protecting group, resulting in the formation of the desired compound, duvelisib (3).
Scheme 2. Preparation of duvelisib (3) from tert-butyl (S)-4-(3-chloro-2-(phenylcarbamoyl)phenyl)-
3-oxobutan-2-ylcarbamate (10).
3. Perspectives
The pharmacological profile of duvelisib (
treatment of several hematological malignancies, indicating that it can be further approved for other
uses beyond CLL, SLL, and FL. The use of duvelisib ( ) for inflammatory and autoimmune diseases
3
) showed the safety and efficacy of this drug in the
3
will be contested by the adverse events that occurred during the clinical trials, but the use of this drug
for these applications probably will depend on the clinical benefit. The usefulness of the modulation
of PI3K can be highlighted by the efforts on the discovery and development of novel PI3K
δ, PI3Kγ,
and PI3Kδ/γ for the treatment of cancer, inflammatory, and autoimmune diseases [22,23].
Author Contributions: Conceptualization, D.A.R., F.S.S. and C.A.M.F.; methodology, D.A.R. and F.S.S.;
investigation, D.A.R. and F.S.S.; resources, D.A.R. and F.S.S.; data curation, D.A.R. and F.S.S.; writing—original
draft preparation, D.A.R. and F.S.S.; writing—review and editing, D.A.R., F.S.S. and C.A.M.F.; visualization,
D.A.R., F.S.S. and C.A.M.F.; supervision, C.A.M.F.; project administration, C.A.M.F.; funding acquisition, C.A.M.F.
All authors read and approved final version of the manuscript.
Funding: This research was funded in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES, BR) - Finance Code 001. The authors would also like to thank National Institute of Science and Technology
in Drugs and Medicines (INCT-INOFAR, BR, Grant No. 465.249/2014-0), Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq, BR, Grant No. 432.001/2016-6), Fundação Carlos Chagas Filho de Amparo à
Pesquisa do Estado do Rio de Janeiro (FAPERJ, BR, Grant No. E-26/201.954/2017 and E-26/202.878/2018) for the
financial support provided and the fellowships awarded.
Conflicts of Interest: The authors declare no conflict of interest.

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References
1.
2.
3.
Markham, A. Idelalisib: First global approval. Drugs 2014, 74, 1701–1707. [CrossRef] [PubMed]
Markham, A. Copanlisib: First Global Approval. Drugs 2017, 77, 2057–2062. [CrossRef] [PubMed]
Scott, W.J.; Hentemann, M.F.; Rowley, R.B.; Bull, C.O.; Jenkins, S.; Bullion, A.M.; Johnson, J.; Redman, A.;
Robbins, A.H.; Esler, W.; et al. Discovery and SAR of novel 2,3-dihydroimidazo[1,2-c]quinazoline PI3K
inhibitors: Identification of copanlisib (BAY 80-6946). ChemMedChem 2016, 11, 1517–1530. [CrossRef]
[PubMed]
4.
5.
Blair, H.A. Duvelisib: First global approval. Drugs 2018, 78, 1847–1853. [CrossRef]
Flinn, I.W.; Hillmen, P.; Montillo, M.; Nagy, Z.; Illes, A.; Etienne, G.; Delgado, J.; Kuss, B.J.; Tam, C.S.;
Gasztonyi, Z.; et al. The phase 3 DUO trial: Duvelisib vs ofatumumab in relapsed and refractory CLL/SLL.
Blood 2018, 132, 2446–2455. [CrossRef]
6.
7.
A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients with Relapsed or Refractory CLL/SLL (DUO).
Available online: https://clinicaltrials.gov/ct2/show/NCT02004522 (accessed on 4 April 2019).
Study of Duvelisib in Combination with Rituximab vs Rituximab in Subjects with Previously Treated
Follicular Lymphoma (DYNAMO + R). Available online: https://clinicaltrials.gov/ct2/show/NCT02204982
(accessed on 4 April 2019).
8.
9.
Walker, E.H.; Perisic, O.; Ried, C.; Stephens, L.; Williams, R.L. Structural insights into phosphoinositide
3-kinase catalysis and signalling. Nature 1999, 402, 313–320. [CrossRef]
Hennessy, B.T.; Smith, D.L.; Ram, P.T.; Lu, Y.; Mills, G.B. Exploiting the PI3K/AKT pathway for cancer drug
discovery. Nat. Rev. Drug Discov. 2005, 4, 988–1004. [CrossRef] [PubMed]
10. Liu, P.; Cheng, H.; Roberts, T.M.; Zhao, J.J. Targeting the phosphoinositide 3-kinase pathway in cancer.
Nat. Rev. Drug Discov. 2009, 8, 627–644. [CrossRef]
11. Thorpe, L.M.; Yuzugullu, H.; Zhao, J.J. PI3K in cancer: Divergent roles of isoforms, modes of activation and
therapeutic targeting. Nat. Rev. Cancer 2015, 15, 7–24. [CrossRef]
12. Garces, A.E.; Stocks, M.J. Class 1 PI3K clinical candidates and recent inhibitor design strategies: A medicinal
chemistry perspective. J. Med. Chem. 2018. [CrossRef]
13. Somoza, J.R.; Koditek, D.; Villasenor, A.G.; Novikov, N.; Wong, M.H.; Liclican, A.; Xing, W.; Lagpacan, L.;
Wang, R.; Schultz, B.E.; et al. Structural, biochemical, and biophysical characterization of idelalisib binding
to phosphoinositide 3-kinase delta. J. Biol. Chem. 2015, 290, 8439–8446. [CrossRef] [PubMed]
14. Miller, M.S.; Thompson, P.E.; Gabelli, S.B. Structural determinants of isoform selectivity in PI3K inhibitors.
Biomolecules 2019, 9, 82. [CrossRef] [PubMed]
15. Winkler, D.G.; Faia, K.L.; DiNitto, J.P.; Ali, J.A.; White, K.F.; Brophy, E.E.; Pink, M.M.; Proctor, J.L.; Lussier, J.;
Martin, C.M.; et al. PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and
suppresses activity in autoimmune and inflammatory disease models. Chem. Biol. 2013, 20, 1364–1374.
[CrossRef]
16. Walker, E.H.; Pacold, M.E.; Perisic, O.; Stephens, L.; Hawkins, P.T.; Wymann, M.P.; Williams, R.L. Structural
determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin,
and staurosporine. Mol. Cell. 2000, 6, 909–919. [CrossRef]
17. Huang, C.H.; Mandelker, D.; Schmidt-Kittler, O.; Samuels, Y.; Velculescu, V.E.; Kinzler, K.W.; Vogelstein, B.;
Gabelli, S.B.; Amzel, L.M. The structure of a human p110alpha/p85alpha complex elucidates the effects of
oncogenic PI3Kalpha mutations. Science 2007, 318, 1744–1748. [CrossRef] [PubMed]
18. Williams, R.; Berndt, A.; Miller, S.; Hon, W.C.; Zhang, X. Form and flexibility in phosphoinositide 3-kinases.
Biochem. Soc. Trans. 2009, 37 Pt 4, 615–626. [CrossRef]
19. Traxler, P.; Furet, P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors.
Pharmacol. Ther. 1999, 82, 195–206. [CrossRef]
20. Berndt, A.; Miller, S.; Williams, O.; Le, D.D.; Houseman, B.T.; Pacold, J.I.; Gorrec, F.; Hon, W.C.; Liu, Y.;
Rommel, C.; et al. The p110 delta structure: Mechanisms for selectivity and potency of new PI(3)K inhibitors.
Nat. Chem. Biol. 2010, 6, 117–124. [CrossRef]
21. Katso, R.; Okkenhaug, K.; Ahmadi, K.; White, S.; Timms, J.; Waterfield, M.D. Cellular function of phosphoinositide
3-kinases: Implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 2001, 17, 615–675.
[CrossRef]

Pharmaceuticals 2019, 12, 69
7 of 7
22. Cushing, T.D.; Metz, D.P.; Whittington, D.A.; McGee, L.R. PI3Kdelta and PI3Kgamma as targets for
autoimmune and inflammatory diseases. J. Med. Chem. 2012, 55, 8559–8581. [CrossRef]
23. Perry, M.W.D.; Abdulai, R.; Mogemark, M.; Petersen, J.; Thomas, M.J.; Valastro, B.; Eriksson, A.W. Evolution
of PI3Kgamma and delta inhibitors for inflammatory and autoimmune diseases. J. Med. Chem. 2018
[CrossRef]
.
24. Ali, A.Y.; Wu, X.; Eissa, N.; Hou, S.; Ghia, J.E.; Murooka, T.T.; Banerji, V.; Johnston, J.B.; Lin, F.; Gibson, S.B.;
et al. Distinct roles for phosphoinositide 3-kinases gamma and delta in malignant B cell migration. Leukemia
2018, 32, 1958–1969. [CrossRef] [PubMed]
25. Flinn, I.W.; O’Brien, S.; Kahl, B.; Patel, M.; Oki, Y.; Foss, F.F.; Porcu, P.; Jones, J.; Burger, J.A.; Jain, N.; et al.
Duvelisib, a novel oral dual inhibitor of PI3K-delta,gamma, is clinically active in advanced hematologic
malignancies. Blood 2018, 131, 877–887. [CrossRef]
26. O’Brien, S.; Patel, M.; Kahl, B.S.; Horwitz, S.M.; Foss, F.M.; Porcu, P.; Jones, J.; Burger, J.; Jain, N.; Allen, K.;
et al. Duvelisib, an oral dual PI3K-delta,gamma inhibitor, shows clinical and pharmacodynamic activity in
chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study. Am. J. Hematol. 2018
93, 1318–1326. [CrossRef] [PubMed]
,
27. Horwitz, S.M.; Koch, R.; Porcu, P.; Oki, Y.; Moskowitz, A.; Perez, M.; Myskowski, P.; Officer, A.; Jaffe, J.D.;
Morrow, S.N.; et al. Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical
models of T-cell lymphoma. Blood 2018, 131, 888–898. [CrossRef] [PubMed]
28. Verastem Inc. Copiktra (Duvelisib), Capsules for Oral Use: US Prescribing Information. 2018. Available online:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf (accessed on 29 April 2019).
29. Flinn, I.W.; Patel, M.; Oki, Y.; Horwitz, S.; Foss, F.F.; Allen, K.; Douglas, M.; Stern, H.; Sweeney, J.; Kharidia, J.;
et al. Duvelisib, an oral dual PI3K-delta, gamma inhibitor, shows clinical activity in indolent non-Hodgkin
lymphoma in a phase 1 study. Am. J. Hematol. 2018, 93, 1311–1317. [CrossRef] [PubMed]
30. Trial of Duvelisib in Combination with Either Romidepsin or Bortezomib in Relapsed/Refractory T-Cell
Lymphomas. Available online: https://clinicaltrials.gov/ct2/show/NCT02783625 (accessed on 4 April 2019).
31. Duvelisib and Venetoclax in Relapsed or Refractory CLL or SLL. Available online: https://clinicaltrials.gov/
ct2/show/NCT03534323 (accessed on 4 April 2019).
32. A Phase 2a, Efficacy and Safety Study of Duvelisib in Mild Asthmatic Subjects. Available online: https:
//clinicaltrials.gov/ct2/show/NCT01653756 (accessed on 4 April 2019).
33. A Double-Blind Study Evaluating Duvelisib in Subjects with Moderate to Severe Rheumatoid Arthritis and
an Inadequate Response to Methotrexate Alone (ASPIRA). Available online: https://clinicaltrials.gov/ct2/
show/NCT01851707 (accessed on 4 April 2019).
34. Ren, P.; Liu, Y.; Wilson, T.E.; Li, L.; Chan, K.; Rommel, C. Certain Chemical Entities, Compositions and
Methods. US2009312319A1, 14 December 2009.
35. Ren, P.; Liu, Y.; Wilson, T.E.; Li, L.; Chan, K.; Rommel, C. Certain Chemical Entities, Compositions and
Methods. WO2011008302A1, 20 January 2011.
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