Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Quintás‐Cardama, Alfonso; Vaddi, Kris; Liu, Phillip; Manshouri, Taghi; Li, Jun; Scherle, Peggy; Caulder, Eian; Wen, Xiaoming; Li, Yanlong; Waeltz, Paul; Rupar, Mark; Burn, Timothy C.; Lo, Yvonne; Kelley, Jennifer; Covington, Maryanne; Shepard, Stacey; Rodgers, James D.; Haley, Patrick J.; Kantarjian, Hagop M.; Fridman, Jordan S.; Verstovšek, Srđan

doi:10.1182/blood-2009-04-214957

Cited by 722 publications

(640 citation statements)

References 32 publications

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“…Coinjection was used to directly assay the effect of type I IFN on rVSV-eGFP spread in the parenchyma. The MDAS, MACS, and LS were significantly reduced ( (37,38). DIPs were coinjected into the CP with the inhibitor mixture 1 d before injection of rVSV-eGFP into the contralateral CP (Fig.…”

Section: Resultsmentioning

confidence: 99%

The brain parenchyma has a type I interferon response that can limit virus spread

Drokhlyansky

Ayturk

Soh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The brain has a tightly regulated environment that protects neurons and limits inflammation, designated "immune privilege." However, there is not an absolute lack of an immune response. We tested the ability of the brain to initiate an innate immune response to a virus, which was directly injected into the brain parenchyma, and to determine whether this response could limit viral spread. We injected vesicular stomatitis virus (VSV), a transsynaptic tracer, or naturally occurring VSV-derived defective interfering particles (DIPs), into the caudate-putamen (CP) and scored for an innate immune response and inhibition of virus spread. We found that the brain parenchyma has a functional type I interferon (IFN) response that can limit VSV spread at both the inoculation site and among synaptically connected neurons. Furthermore, we characterized the response of microglia to VSV infection and found that infected microglia produced type I IFN and uninfected microglia induced an innate immune response following virus injection.

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Section: Resultsmentioning

confidence: 99%

The brain parenchyma has a type I interferon response that can limit virus spread

Drokhlyansky

Ayturk

Soh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…14,15 To ensure target inhibition over 24 h in the Ba/F3-JAK2 V617F disease model, the PK profile was determined in this model (Supplementary Figure S1) and a maximum dose of 150 mg/kg p.o. q.d.…”

Section: Therapeutic Effects Of Sb1518 In a Jak2 V617f -Dependent Xenmentioning

confidence: 99%

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

Hart¹,

Goh²,

et al. 2011

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SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC 50 ¼ 23 and 19 nM for JAK2 WT and JAK2 V617F , respectively) within the JAK family (IC 50 ¼ 1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC 50 ¼ 22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2 V617F -driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/ STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2 V617F patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.

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“…Ruxolitinib is a pan-JAK inhibitor that strongly inhibits JAK1 as well as JAK2 phosphorylation. 9 Its approval was based on the results of 2 phase 3 studies, COMFORT-I and COMFORT-II, which demonstrated efficacy by reduction in splenomegaly and symptom improvement. Anemia, often requiring transfusions, and dose-related thrombocytopenia were the most clinically significant and dose-limiting toxicities.…”

Section: Introductionmentioning

confidence: 99%

Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis

Komrokji

Seymour

Roberts

et al. 2015

Blood

109

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Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms

Cited by 722 publications

References 32 publications

The brain parenchyma has a type I interferon response that can limit virus spread

The brain parenchyma has a type I interferon response that can limit virus spread

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis

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