Inhibition of JAK3 with a novel, selective and orally active small molecule induces therapeutic response in T-cell malignancies

Ross, Jeremy A.; Spadaro, Michela; Rosado, Damaris C.; Cavallo, Federica; Kirken, Robert A.; Pericle, Federica

doi:10.1038/leu.2013.309

Cited by 14 publications

(14 citation statements)

References 15 publications

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“…30 As a further control, we also used a Ba/F3 cell line transformed by TEL- Abelson murine leukemia viral oncogene homolog (ABL). To enable a direct comparison with the commonly used JAK inhibitors we profiled reported compounds 1 – 5 , 4–5, 15b, 15g, 31 and 12 32 against this panel of Ba/F3 cells. Compound 1 exhibited the most potent inhibition of JAK1 and JAK2 Ba/F3 cells, 2 exhibited most potent inhibition of JAK3 Ba/F3 cells and 3 exhibited most selective inhibition of JAK3 (Table S2).…”

Section: Resultsmentioning

confidence: 99%

“…Numerous ATP-competitive JAK3 inhibitors have been developed (Figure 1A). 15 Tofacitinib ( 2 ) was developed as a specific JAK3 inhibitor to prevent organ-transplant rejection but subsequent studies revealed that it is also a potent inhibitor of JAK1 and JAK2. 5, 16 The combination of compound 2 ’s excellent potency, selectivity and pharmacological properties have made it a favored inhibitor to interrogate JAK kinase activity in numerous biological models.…”

Section: Introductionmentioning

confidence: 99%

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Development of Selective Covalent Janus Kinase 3 Inhibitors

Akahane

McNally

et al. 2015

J. Med. Chem.

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The Janus Kinases (JAKs) and their downstream effectors Signal Transducer and Activator of Transcription proteins (STATs) form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation and hematopoiesis and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity-relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å co-crystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of Selective Covalent Janus Kinase 3 Inhibitors

Akahane

McNally

et al. 2015

J. Med. Chem.

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“…The Mannich base NC1153 and its derivative, EP-009, have been shown to be selective in targeting Jak3 resulting in reduced tyrosine kinase activity and induction of apoptosis in Jak3 expressing lymphocytes [3, 4, 13]. Similarly, CP-690,550 has been shown to be an effective driver of apoptosis in a Jak3 transformed Ba/F3 model but also has inhibitory effects on Jak1 and Jak2 [14].…”

Section: Resultsmentioning

confidence: 99%

“…Transformed Ba/F3 cells were seeded into 96 well plates at a density of 10 4 cells per 100 μL. They were then treated at a range of 0 to 500 nM with CP-690,550 (Selleck Chemicals), 0 to 10 μM with NC1153 [3] or 0 to 10 μM with EP-009 [4] for 24 hours at 37 °C. Cellular viability was then determined by MTS assay (Promega) according to the manufacturer’s instructions in triplicate (n=3).…”

Section: Methodsmentioning

confidence: 99%

“…This is especially true in T-, B- and Natural Killer cells where Jak3 is predominantly expressed [3]. Loss of Jak3 regulation in immune cells leads to diseases including Severe Combined Immunodeficiency (SCID) [4, 5], and cancers of the blood, such as leukemia and lymphoma [6, 7]. Hematological cancers have been previously reported to be associated with Jak3 gain of function mutations [7–10].…”

Section: Introductionmentioning

confidence: 99%

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Transforming Mutations of Jak3 (A573V and M511I) Show Differential Sensitivity to Selective Jak3 Inhibitors

Martinez

Ross

Kirken

2016

CCAND

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Background A medical need exists for successfully treating patients afflicted with leukemia and especially those that relapse and ultimately become refractory to front line chemotherapies. Leukemia cases are particularly high within Hispanic populations where this disease is among the most frequently occurring cancer. A possible cause is somatic mutations in Janus tyrosine kinase (Jak3). Fourteen somatic mutations have been reported in Jak3, including M511I and A573V, from patients with various forms of leukemia. While several of these Jak3 mutations have been shown to possess transforming ability in cell lines, whether these mutations are susceptible to Jak3 selective inhibitors remains less clear. Methods The IL-3 dependent pro-B cell line Ba/F3 was virally transduced with plasmids encoding GFP and different mutant forms of Jak3, some of which conferred IL-3 independence. Sensitivity to pre-clinical and clinical Jak3 selective inhibitors was assessed for cellular viability and growth. Results Two Jak3 mutations conferred IL-3 independent growth in Ba/F3 cells. However, the level of drug sensitivity varied with respect to Jak3 inhibitors NC1153, CP-690,550, and EP-009. Conclusion Jak3 inhibitors CP-690,550 and NC1153 showed efficacy in reducing viability of Ba/F3 cells transformed with mutant forms of Jak3, thus providing new therapeutic strategies to treat these types of cancer.

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