Drugs in Clinical Pipeline: RO-9021

RO-9021 [(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide] is an oral, ATP-competative and selective inhibitor of spleen tyrosine kinase (SYK). RO-9021 potently inhibited SYK kinase activity with an average IC₅₀ of 5.6 nM. Selectivity of RO-9021 against a panel of 451 wild-type and mutant protein kinases was assessed using an ATP binding site competition assay developed by KINOMEscan Inc.  

RO-9021 is a highly selective SYK inhibitor with low S-scores of 0.003 for S(99) and 0.015 for S(90), indicating that SYK is the only kinase with 99% competition with RO-9021 (1 uM) in a total of 392 tested kinases. There were only a total of seven kinases (JAK1, JAK3, GCN2, SLK, FLT3(ITD), PAK2) including SYK, having more than 90% competition with RO9021. It inhibited JAK1 and JAK3 with 97% at 1 uM.

References:

1. Liao, C.; et. al. Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy. Arthritis Res Ther 2013, 15(5), R146.

Drugs in Clinical Pipeline: GSK143

GSK143 [2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide] is a potent and highly selective spleen tyrosine kinase (SYK) inhibitor (pIC₅₀ = 7.5) showing good efficacy in the rat Arthus model. The selectivity profile of GSK143 was determined against a panel of 66 protein kinases and none were inhibited within 10-fold of SYK activity. GSK143 is greater than 600-fold selective for SYK over ZAP-70 (pIC₅₀ = 4.7), the other member of the SYK kinase family [1].

The activity of GSK143 is as follows:

pIC₅₀(SYK enzyme assay) = 7.5

pIC₅₀(ZAP-70 enzyme assay) = 4.7

pIC₅₀(LCK enzyme assay) = 5.3

pIC₅₀(LYN enzyme assay) = 5.4

pIC₅₀(JAK1 enzyme assay) = 5.8

pIC₅₀(JAK2 enzyme assay) = 5.8

pIC₅₀(JAK3 enzyme assay) = 5.7

pIC₅₀(AURKB enzyme assay) = 4.8

Common Name: GSK143

Synonyms: GSK143; GSK-143; GSK 143

IUPAC Name: 

CAS Number: 1240390-27-5

SMILES:

Mechanism of Action: Kinase Inhibitor; SYK Inhibitor; Spleen Kinase Inhibitor

Indication: Various Cancers; Anti-inflammatory Drugs

Development Stage: Investigational

Company: GlaxoSmithKline

The progression of GSK143 was terminated due to a mutagenicity risk highlighted in the Ames assay, it remains one of the most selective SYK inhibitors disclosed to date and hence an excellent tool molecule for further evaluation of the SYK mechanism.

References:
1. Liddle, J.; et. al. Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor. Bioorg Med Chem Lett 2011, 21(20), 6188-6194.

Drugs in Clinical Pipeline: PRT062607

PRT062607 [4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide] is a novel, highly specific, and potent orally available small-molecule inhibitor of Spleen Tyrosine Kinase (Syk). The potency of PRT062607 against its target kinase Syk was initially tested in two different purified kinase assays. Using a FRET assay, half-maximal Syk inhibition (IC₅₀) required 6 ± 0.2 nM. Similar potency was observed when tested in a radioactive enzyme assay, with a resulting Syk IC₅₀ of 2.1 ± 0.4 nM [1].

The specificity of PRT062607 was tested in a panel of 270 independent purified kinase assays at 300 nM.  At this concentration, Syk and 8 other kinases (Fgr, MLK1, Yes, Flt3, PAK5, Lyn, Src, Lck) were inhibited by greater than 80%.  Subsequent analysis demonstrated a Syk IC₅₀ of 1 nM, whereas the next most potently inhibited kinase, Fgr required an IC₅₀ of 81 nM. PRT062607 also showed substantially weaker inhibitory potency against the three kinases most homologous to Syk; namely, focal adhesion kinase (FAK), protein tyrosine kinase 2 (PTK2), and Zap70 (IC₅₀ = 415, 108 and 1050 nM, respectively) [2, 3].  In a variety of cellular assays researchers observed potent inhibition of B cell receptor (BCR) induced Syk signaling, but not of Lyn, phorbol 12-myristate 13-acetate (PMA) induced protein kinase C, T cell receptor induced Zap70, or cytokine induced JAK1 (IL6), JAK2 (GM-CSF), or JAK1/3 (IL4) dependent STAT phosphorylation.  Consistently, in Ba/F3 cell lines transformed by various kinases, PRT062607 only inhibited proliferation of those cells transformed by Syk (IC₅₀ = 0.12 µM), and not by Zap70 or JAK family members (IC₅₀ greater than 6 µM).  In human whole blood, PRT062607 suppressed BCR-induced Syk signaling and cellular activation with IC₅₀’s of 0.383 µM and 0.362 µM, respectively. FceR1-induced basophil degranulation was similarly suppressed with an IC₅₀ of 0.171 µM [3].

On Oct 27, 2011 Biogen Idec and Portola Pharmaceuticals entered into a licensing agreement to develop and commercialize PRT062607, for the treatment of rheumatoid arthritis as well as other autoimmune and inflammatory diseases. Biogen Idec will lead the global programme in major indications such as rheumatoid arthritis, whereas Portola will lead development and commercialization efforts in the United States for smaller indications, as well as discovery efforts for follow-on SYK inhibitors. Portola retains an option to co-promote alongside Biogen Idec in the United States in major indications. Worldwide costs and profits will be split by Biogen and Portola 75 percent and 25 percent, respectively.

The activity of PRT062607 is as follows:

IC₅₀ (SYK enzyme assay, FRET assay) = 6 ± 0.2 nM

IC₅₀ (SYK enzyme assay, Radioactive enzyme assay) = 2.1 ± 0.4 nM; 1 nM

IC₅₀ (FGR enzyme assay) = 81 nM

IC₅₀ (MLK1 enzyme assay) = 88 nM

IC₅₀ (YES enzyme assay) = 123 nM

IC₅₀ (FLT3 enzyme assay) = 139 nM

IC₅₀ (PAK5 enzyme assay) = 166 nM

IC₅₀ (Lyn enzyme assay) = 192 nM

IC₅₀ (c-Src enzyme assay) = 244 nM

IC₅₀ (LCK enzyme assay) = 249 nM

Common Name: PRT062607

Synonyms: PRT-062607; PRT 062607; PRT062607; P505-15, BIIB057

IUPAC Name: 4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino)pyrimidine-5-carboxamide

CAS Number: 1370261-96-3; 1370261-97-4 (hydrochloride); 1370261-98-5 (acetate)

SMILES:NC(C(C=NC(N[C@@H]1CCCC[C@@H]1N)=N2)=C2NC3=CC(N4N=CC=N4)=CC=C3)=O

Mechanism of Action: Kinase Inhibitor; SYK Inhibitor

Indication: Anti-inflammatory Agents; Treatment of Rheumatoid arthritis; Various Cancers

Development Stage: Phase I /II

Company: Portola Pharmaceuticals/Biogen Idec

Spleen tyrosine kinase (Syk) is broadly involved in regulating leukocyte immune function, principally by facilitating cellular activation in response to receptor engagement of antigen or immune complex. Receptors that use Syk for signal transduction include the B cell antigen receptor (BCR), Fc receptors, integrins, and members of the lectin and selectin families. Each of these Syk-dependent functions in various cell types is likely to be important in the etiology of inflammatory and autoimmune diseases. Syk is therefore considered an important target for controlling diseases involving immune cells. Recent evidence suggests that B-cell malignancies including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) can be driven by aberrant activity of cellular signaling pathways and by extrinsic factors from the microenvironment that interact with the BCR. Increased SYK expression and/or activity has been implicated in a number of NHL histologies [1,2].

Oral administration of PRT062607 in mice led to a reversible inhibition of Syk, with an IC₅₀ of 0.282 µM as determined by an ex vivo whole blood BCR stimulation assay.  Moreover, PRT062607 was tested for its immunomodulatory potential of specific Syk inhibition in vivo using rodent models of rheumatoid arthritis. Oral administration of PRT062607 resulted in statistically significant and dose-dependent anti-inflammatory activity in both the mouse collagen antibody-induced arthritis and rat collagen induced arthritis models.  In each case, anti-inflammatory effects were achieved at sub-micromolar plasma concentrations in which Syk specificity was maintained [3].

With Fostamatinib (R788) bowing out of the race against rheumatoid arthritis due to its promiscuous nature for other kinase targets along with Syk, the hopes are now on PRT062607.  PRT062607 is claimed to be more selective than Fostamatinib with direct support for Syk as a target, whereas for Fostamatinib it was not certain whether efficacy and toxicity were coming primarily from Syk inhibition. However, a planned phase II trial in rheumatoid arthritis was withdrawn prior to patient enrollment [4].

References:

1. Coffey, G.; et. al. Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J Pharmacol Exp Ther 2012,  340(2), 350-359.

2. Spurgeon, S. E.; et. al. The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. J Pharmacol Exp Ther 2013, 344(2), 378-387.

3. Coffey, G.; et. al. 1727 Specific Inhibition of Syk Suppresses Leukocyte Immune Function and Alleviates Inflammation In Rodent Models of Rheumatoid Arthritis. 53rd ASH Annual Meeting and Exposition, Dec 10-13, 2011.
4. ClinicalTrials.gov BIIB057 in Subjects With Rheumatoid Arthritis and Inadequate Response to Disease-Modifying Antirheumatic Drugs (EMBRACE). NCT01652937 (retrieved 01-Oct-2015)

Drugs in Clinical Pipeline: Fostamatinib

Fostamatinib [[6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate] is an oral prodrug that is rapidly converted to a molecule named Tamatinib (or R406), which is potent and relatively selective inhibitor of Spleen tyrosine kinase (Syk). 

Tamatinib is an ATP-competitive inhibitor of biochemical Syk activity (K_i = 30 nM). The IC₅₀ for this compound is 41 nM, and it inhibits 78% of Syk activity at a concentration of 0.3 uM. Tamatinib also inhibits the isolated enzymes Lyn (IC₅₀ = 63 nM) and Lck (IC₅₀ = 37 nM). Tamatinib have potent anti-inflammatory activity, suggesting a role for Syk inhibition in the treatment of rheumatoid arthritis [1].

Despite similar IC₅₀ values on isolated kinases, Tamatinib shows selectivity in cell-based assays. In mast cells activated by FcεRI-crosslinking, the compound is 20-fold more potent for inhibition of linker for activation of T cells (LAT) tyrosine residue Y191 phosphorylation (a Syk kinase substrate; EC₅₀ approximately 0.08 uM) compared with phosphorylation of Syk itself at the Y352 residue (a Lyn substrate; EC₅₀ greater than 2 uM). Moreover, Tamatinib was identified as a potent inhibitor of FcεRI -dependent mast cell activation (EC₅₀ = 43 nM) in primary human mast cells [1].

Rigel Pharmaceuticals is credited with discovering Tamatinib and Fostamatinib. AstraZeneca announced an exclusive worldwide license agreement with Rigel Pharmaceuticals in February 2010 for the global development and commercialization of Fostamatinib. On June 4, 2013, Astra Zeneca announced they were giving up future development on the compound, and terminated their license with Rigel after early results from a Phase IIb study for Rheumatoid Arthritis.

On Sept 8, 2015 Rigel Pharmaceuticals, Inc. discosed that U.S. Food and Drug Administration (US-FDA) has granted Orphan Drug designation to Fostamatinib, Rigel's oral spleen tyrosine kinase inhibitor which is currently in Phase 3 clinical studies in patients with chronic immune thrombocytopenic purpura or ITP. Rigel's Phase 3 program for Fostamatinib in ITP, called FIT, has surpassed the half-way point in enrollment and Rigel expects the program to read out results in mid-2016.

About ITP

Immune Thrombocytopenic Purpura (ITP) is an autoimmune disease where the immune system attacks and destroys platelets in the blood. This results in abnormally low platelet counts. 

There are two forms of ITP:

a: acute thrombocytopenic purpura, which is most commonly seen in young children;

b: chronic thrombocytopenic purpura, which requires continual follow up care with a hematologist.


50,000-60,000 people suffer from chronic ITP-the majority are women. Antibodies, usually of the IgG type, mediate platelet destruction in ITP. Fostamatinib has a novel mechanism of action, blocking IgG receptor signaling in both macrophages and B cells via SYK kinase.

The activity of Tamatinib is as follows:

IC₅₀ (SYK enzyme assay) = 41 nM; K_i = 30 nM

IC₅₀ (LYN enzyme assay) = 63 nM

IC₅₀ (LCK enzyme assay) = 37 nM

Common Name: Fostamatinib

Synonyms: R935788; R 935788; R-935788; R788; R 788, R-788

IUPAC Name: [6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate

CAS Number: 901119-35-5; 1025687-58-4 (disodium salt)

SMILES: 

Mechanism of Action: Kinase Inhibitor; SYK Inhibitor

Indication: Various Cancers; Anti-inflammatory Agents; Treatment for Rheumatoid Arthritis (withdrawn); Treatment for Immune Thrombocytopenic Purpura

Development Stage: Phase III

Company: Rigel Pharmaceuticals

Common Name: Tamatinib

Synonyms: R406; R-406; R 406

IUPAC Name: [6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

CAS Number: 841290-80-0

SMILES: 

Mechanism of Action: Kinase Inhibitor; SYK Inhibitor

Indication: Various Cancers; Anti-inflammatory Agents; Treatment for Rheumatoid Arthritis (withdrawn); Treatment for Immune Thrombocytopenic Purpura

Development Stage: Phase III

Company: Rigel Pharmaceuticals

References:
1. Braselmann, S.; et. al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006, 319(3), 998-1008.

Drugs in Clinical Pipeline: Cerdulatinib

Cerdulatinib [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino) pyrimidine-5-carboxamide], is an orally active kinase inhibitor that demonstrates activity against spleen tyrosine kinase (SYK, IC₅₀ = 32 nM) and Janus kinase (JAK1, 2, 3 IC₅₀ = 12, 6, 8 nM, respectively) [1].

Dual inhibition of SYK and JAK represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity.

Cerdulatinib behaves like a multikinase inhibitor as in specificity assays it showed affinity towards other kinases also. It inhibited nearly 25 tested kinases with IC₅₀ less than 200 nM. Cerdulatinib blocks the B-cell receptor pathway via Syk and cytokine pathways via JAK 1, 3 and Tyk 2, hence it has a unique profile where it inhibits two validated tumor proliferation pathways that contribute to tumor cell growth and survival in certain hematologic malignancies. Moreover, Cerdulatinib has a favorable pharmacokinetic profile with a half-life of 14-18 hours that supports once-daily dosing. There parameters suggest that Cerdulatinib can be used in treatment of patients with genetically-defined hematologic cancers, as well as those who have failed therapy due to relapse or acquired mutations.

Cerdulatinib was discovered at Portola Pharmaceuticals. A Phase 1/2a study involving Cerdulatinib is ongoing in chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma (NHL) patients. Results of in vitro studies suggest that the anti-tumor activity of Cerdulatinib is mediated by dual inhibition of Syk and JAK signaling pathways, and that Cerdulatinib may be a potent treatment for diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin’s lymphoma (NHL). Cerdulatinib also has shown in vitro efficacy in ibrutinib-resistant chronic lymphocytic leukemia (CLL) and in DLBCL with certain mutations.

The activity of Cerdulatinib is as follows:

IC₅₀ (SYK enzyme assay) = 32 nM

IC₅₀ (JAK1 enzyme assay) = 12 nM

IC₅₀ (JAK2 enzyme assay) = 6 nM

IC₅₀ (JAK3 enzyme assay) = 8 nM

IC₅₀ (TYK2 enyme assay) =  0.5  nM

IC₅₀ (MST1 enyme assay) = 4  nM

IC₅₀ (ARK5 enyme assay) = 4  nM

IC₅₀ (MLK1 enyme assay) = 5  nM

IC₅₀ (Fms enyme assay) = 5  nM

IC₅₀ (AMPK enyme assay) = 6  nM

IC₅₀ (TBK1 enyme assay) = 10  nM

IC₅₀ (MARK1 enyme assay) = 10  nM

IC₅₀ (PAR1B-a enyme assay) = 13  nM

IC₅₀ (TSSK enyme assay) = 14  nM

IC₅₀ (MST2 enyme assay) = 15  nM

IC₅₀ (GCK enyme assay) = 18  nM

IC₅₀ (JNK3 enyme assay) = 18  nM

IC₅₀ (RSK2 enyme assay) = 20  nM

IC₅₀ (RSK4 enyme assay) = 28  nM

IC₅₀ (Chk1 enyme assay) = 42  nM

IC₅₀ (FLT4 enyme assay) = 51  nM

IC₅₀ (FLT3 enyme assay) = 90  nM

IC₅₀ (RET enyme assay) = 105  nM

IC₅₀ (ITK enyme assay) = 194  nM

Common Name: Cerdulatinib

Synonyms:  PRT2070; PRT-2070; PRT 2070; PRT-062070; PRT 062070; PRT062070

IUPAC Name: 4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino) pyrimidine-5-carboxamide

CAS Number: 1198300-79-6

Mechanism of Action: Kinase Inhibitor; Dual-Kinase Inhibitor; SYK Inhibitor; JAK Inhibitor

Indication: Various Cancers; Chronic Lymphocytic Leukemia; B-cell Non-Hodgkin Lymphoma

Development Stage: Phase II

Company: Portola Pharmaceuticals

In cellular assays Cerdulatinib demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/3. Limited inhibition of JAK2 was observed, and Cerdulatinib did not inhibit phorbol 12-myristate 13-acetate-mediated signaling or activation in B and T cells nor T-cell antigen receptor-mediated signaling in T cells, providing evidence for selectivity of action. Potent antitumor activity was observed in a subset of B-cell lymphoma cell lines. After oral dosing, Cerdulatinib suppressed inflammation and autoantibody generation in a rat collagen-induced arthritis model and blocked B-cell activation and splenomegaly in a mouse model of chronic B-cell antigen receptor stimulation [1].      

References:
1. Coffey, G.; et. al. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther 2014, 351(3), 538-548.  

Drugs in Clinical Pipeline: Entospletinib

Entospletinib [6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine] is an orally available, ATP competitive and highly selective Spleen tyrosine kinase (Syk) inhibitor which is being developed for treating autoimmune and oncology conditions. Broad kinase panel screening revealed a greater selectivity of entospletinib vs R406. Dissociation constant (K_d) determinations of the strongest hits from the broad panel KINOMEscan showed that aside from Syk itself, only 1 kinase, TNK1, had a K_d less than 100 nM for Entospletinib, whereas 79 kinases had K_d less than 100 nM for R406. In healthy volunteers, Entospletinib at BID doses higher than 200 mg demonstrated inhibition of Syk activity, as measured by CD63 expression and phospho-Syk. Due to its excellent selectivity profile, Entospletinib was hypothesized to provide high levels of Syk inhibition with potentially fewer off-target adverse effects (AEs) than observed with Fostamatinib [1, 2].

The activity of Entospletinib is as follows:

IC₅₀ (Syk enzyme assay) = 7.7 nM
IC₅₀ (pBLNK) = 26 nM

Common Name: Entospletinib

Synonyms:  GS-9973;  GS 9973; GS9973

IUPAC Name: 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine

CAS Number: 1229208-44-9

Mechanism of Action: Kinase Inhibitor; Syk Inhibitor; Spleen Tyrosine Kinase Inhibitor

Indication: Various Cancers; Autoimmune diseases

Development Stage: Phase I/II

Company: Gilead Sciences

Spleen tyrosine kinase (Syk) is a 72 kDa multiple-domain intracellular cytoplasmic tyrosine kinase that is expressed primarily in hematopoietic cells (e.g., B-cells, monocytes, macrophages, mast cells, and neutrophils), where it is recognized as an important mediator of immunoreceptor signaling and has been identified as a potential therapeutic target in allergic, autoimmune, and oncology indications. Immunoreceptor engagement triggers phosphorylation of a pair of tyrosine residues in the cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs) by Src family members, and Syk is recruited to the phosphorylated ITAMs via its SH2 domain.4-6 Syk critically regulates immune cell function by propagating signaling cascades through phosphorylation of direct targets (such as BLNK/SLP65), leading to activation of downstream pathways, including PI3K, MAPK, Btk, and PLCγ. The activation of these pathways in immune cells leads to proliferation, differentiation, cytoskeletal remodeling, and cytokine release. Importantly, since Syk is not expressed in mature T-cells, the immunosuppression that is associated with therapeutics that inhibit T-cell signaling should be avoided.

Entospletinib shows better kinase selectivity and oral availability than the most advanced Syk inhibitor, R406, (or its prodrug form Fostamatinib). R406 has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of R406. TNK1 is the only kinase that has less than 10-fold selectivity versus Syk for Entospletinib, whereas R406 bound 36 kinases within 10-fold of the potency of Syk and 14 kinases more potently than Syk [1]. 

References:

1. Currie, K. S.; et. al. Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. J Med Chem 2014, 57(9), 3856-3873.
2. Sharman, J.; et. al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood 2015, 125(15), 2336-2343

3. ClinicalTrials.gov A Phase 1 Study of Novel GS-9973 Tablet Formulations to Evaluate the Effect of Acid Reducing Agents, Relative Bioavailability, and Food Effect on GS-9973 Pharmacokinetics. NCT01841489 (retrieved 25-04-2015)

4. ClinicalTrials.gov A Phase 2 of Entospletinib in Subjects With Relapsed or Refractory Hematologic Malignancies. NCT01799889 (retrieved 25-04-2015)

5. ClinicalTrials.gov  A Phase 2 of GS-9973 in Combination With Idelalisib in Subjects With Relapsed or Refractory Hematologic Malignancies. NCT01796470 (retrieved 25-04-2015)