Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Zhong, Yun‐Shi; Dong, Shuai; Strattan, Ethan; Li, Ren; Butchar, Jonathan P.; Thornton, Kelsey; Mishra, Anjali; Porcu, Pierluigi; Bradshaw, J. Michael; Bisconte, Angelina; Owens, Timothy D.; Verner, Erik; Brameld, Ken A.; Funk, Jens Oliver; Hill, Ronald J.; Johnson, Amy J.; Dubovsky, Jason A.

doi:10.1074/jbc.m114.614891

Cited by 37 publications

(37 citation statements)

References 66 publications

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“…1A) (15). Based on in vitro kinase assays, PRN694 is a potent inhibitor of all three Tec kinases expressed in T cells, demonstrates less potency toward the other Tec kinases BTK and BMX (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Based on in vitro kinase assays, PRN694 is a potent inhibitor of all three Tec kinases expressed in T cells, demonstrates less potency toward the other Tec kinases BTK and BMX (Fig. 1B), and shows excellent kinome-wide selectivity (15). As reported, PRN694 binds covalently to a conserved cysteine residue in the ATP binding sites of ITK and RLK (ITK C442, RLK C350), and is highly selective for these two kinases in T cells (15).…”

Section: Resultsmentioning

confidence: 99%

“…1B), and shows excellent kinome-wide selectivity (15). As reported, PRN694 binds covalently to a conserved cysteine residue in the ATP binding sites of ITK and RLK (ITK C442, RLK C350), and is highly selective for these two kinases in T cells (15). Unlike its binding to ITK and RLK, PRN694 does not appear to bind covalently to BTK and hence displays a limited duration of BTK inhibition biochemically and in cells (15).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the transferred cells, mice received vehicle alone or PRN694 by oral gavage. Based on studies of ITK target occupancy in thymocytes following in vivo administration of PRN694 in mice (15), we dosed mice daily, and for a two-week period (weeks 2–4), twice daily (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

“…A more direct strategy to address ITK and/or RLK function in T cells is to utilize a selective small molecule inhibitor of these Tec kinases. PRN694 is a small molecule that forms an irreversible covalent bond with C442 in ITK or C350 in RLK, and has recently been shown to selectively inhibit ITK and RLK in T cells (15). To date, the inhibitory effects of PRN694 on CD4 + T helper cell differentiation and effector function have not been tested.…”

Section: Introductionmentioning

confidence: 99%

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A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

Cho

Shin

Haberstock-Debić

et al. 2015

The Journal of Immunology

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In T cells, the Tec kinases ITK and RLK are activated by TCR stimulation, and are required for optimal downstream signaling. Studies of CD4+ T cells from Itk−/− and Itk−/− Rlk−/− mice have indicated differential roles of ITK and RLK in TH1, TH2, and TH17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. Here, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro TH polarization experiments indicate that PRN694 is a potent inhibitor of TH1 and TH17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-γ production by colitogenic CD4+ T cells. Consistent with these findings, TH1 and TH17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in TH1-mediated inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

Cho

Shin

Haberstock-Debić

et al. 2015

The Journal of Immunology

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Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis

Lechner

Weigmann

2020

J Mol Med

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ITK (IL-2-inducible tyrosine kinase) belongs to the Tec family kinases and is mainly expressed in T cells. It is involved in TCR signalling events driving processes like T cell development as well as Th2, Th9 and Th17 responses thereby controlling the expression of pro-inflammatory cytokines. Studies have shown that ITK is involved in the pathogenesis of autoimmune diseases as well as in carcinogenesis. The loss of ITK or its activity either by mutation or by the use of inhibitors led to a beneficial outcome in experimental models of asthma, inflammatory bowel disease and multiple sclerosis among others. In humans, biallelic mutations in the ITK gene locus result in a monogenetic disorder leading to T cell dysfunction; in consequence, mainly EBV infections can lead to severe immune dysregulation evident by lymphoproliferation, lymphoma and hemophagocytic lymphohistiocytosis. Furthermore, patients who suffer from angioimmunoblastic T cell lymphoma have been found to express significantly more ITK. These findings put ITK in the strong focus as a target for drug development.

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Advances and Perspectives in the Treatment of T-PLL

Braun

Jan

Wahnschaffe

et al. 2020

Curr Hematol Malig Rep

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Purpose of Review T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumabbased induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies. Recent Findings Alemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CART cell therapy are at the stage of pre-clinical assessments of activity and feasibility. Summary The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-inhuman results in T-PLL, and urgently have to be transferred to systematic clinical testing.

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Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Cited by 37 publications

References 66 publications

A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis

Advances and Perspectives in the Treatment of T-PLL

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