scholarly journals Suppression of Pyk2 Kinase and Cellular Activities by Fip200

2000 ◽  
Vol 149 (2) ◽  
pp. 423-430 ◽  
Author(s):  
Hiroki Ueda ◽  
Smita Abbi ◽  
Chuanhai Zheng ◽  
Jun-Lin Guan
Keyword(s):  
Tyrosine Kinase ◽  
Intracellular Signaling ◽  
Kinase Activity ◽  
Inhibitory Effect ◽  
Kinase Domain ◽  
Immunofluorescent Staining ◽  
Intact Cells ◽  
Interacting Protein ◽  
Tyrosine Kinase 2

Proline-rich tyrosine kinase 2 (Pyk2) is a cytoplasmic tyrosine kinase implicated to play a role in several intracellular signaling pathways. We report the identification of a novel Pyk2-interacting protein designated FIP200 (FAK family kinase–interacting protein of 200 kD) by using a yeast two-hybrid screen. In vitro binding assays and coimmunoprecipitation confirmed association of FIP200 with Pyk2, and similar assays also showed FIP200 binding to FAK. However, immunofluorescent staining indicated that FIP200 was predominantly localized in the cytoplasm. FIP200 bound to the kinase domain of Pyk2 and inhibited its kinase activity in in vitro kinase assays. FIP200 also inhibited the kinase activity of the Pyk2 isolated from SYF cells (deficient in Src, Yes, and Fyn expression) and the Pyk2 mutant lacking binding site for Src, suggesting that it regulated Pyk2 kinase directly rather than affecting the associated Src family kinases. Consistent with its inhibitory effect in vitro, FIP200 inhibited activation of Pyk2 and Pyk2-induced apoptosis in intact cells, which correlated with its binding to Pyk2. Finally, activation of Pyk2 by several biological stimuli correlated with the dissociation of endogenous FIP200–Pyk2 complex, which provided further support for inhibition of Pyk2 by FIP200 in intact cells. Together, these results suggest that FIP200 functions as an inhibitor of Pyk2 via binding to its kinase domain.

scholarly journals CSIG-31. ALTERNATIVE RECEPTOR TYROSINE KINASE SIGNALING AS A RESISTANCE MECHANISM TO ERK INHIBITION IN HIGH-GRADE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi50-vi51
Author(s):  
Ann-Catherine Stanton ◽  
Robert Koncar ◽  
Brian Golbourn ◽  
Michelle Wassell ◽  
Nishant Agrawal ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Protein Level ◽  
Resistance Mechanisms ◽  
Kinase Domain ◽  
High Grade ◽  
Transactivation Domain ◽  
Tyrosine Kinase 2 ◽  
High Grade Gliomas

Abstract Pediatric High-Grade Gliomas (PHGG), which include Diffuse Midline Gliomas (DMG), are a leading cause of brain tumor death in children. Our recent work has identified extracellular signal-regulated kinase 5 (ERK5) as a critical mediator of cell survival in PHGG. Suppression of ERK5 genetically or pharmacologically leads to decreased cell proliferation and increased apoptosis both in vitro and in vivo in multiple PHGG and H3K27M mutant DMG cell lines. Mechanistically, we show that ERK5 directly stabilizes the proto-oncogene MYC at the protein level, providing rationale to clinically target ERK5. ERK5 contains both a kinase domain (KD) and a transactivation domain (TAD), unlike all other ERKs. Unexpectedly, we found that our ERK5 depleted cells could be partially rescued by an ERK5 kinase domain dead (ERK5-KDD) but TAD intact construct. Additionally, persistent ERK5 depletion does not result in complete growth inhibition and therefore we set out to determine potential adaptation or resistance mechanisms in response to ERK5 loss. To address this, we performed RNA sequencing of DMG cells, comparing control cells to ERK5 knockdown cells, and performed gene-ontology (GO) pathway analysis to identify transcriptional changes that occur in response to ERK5 depletion. We identified 105 differentially expressed genes, and GO analysis identified alternative receptor tyrosine kinase (RTK) gene-expression as one of the top biological processes upregulated in response to ERK5 loss. We validated our top targets at the RNA and the protein level. Our top targets were Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) and Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), both clinically actionable targets. Our future work will focus on functional validation of these RTKs as potential resistance mechanisms to ERK5 loss. Identification of resistance mechanisms to ERK5 loss will have both biological and translational relevance and may lead to effective therapeutic combinations.

Inhibition by two lavendustins of the tyrosine kinase activity of pp60F527 in vitro and in intact cells

1994 ◽  
Vol 269 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Wenceslas K. Agbotounou ◽  
Kazuo Umezawa ◽  
Alain Jacquemin-Sablon ◽  
Josiane Pierre
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Tyrosine Kinase Activity ◽  
Intact Cells

Leukemic Stem Cells of Chronic Phase CML Patients Possess Uniquely Elevated BCR-ABL Kinase Activity and Acquire Spontaneous BCR-ABL Kinase Domain Mutations at a High Frequency.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 438-438 ◽  
Author(s):  
Xiaoyan Jiang ◽  
Kyi Min Saw ◽  
Allen Eaves ◽  
Connie Eaves
Keyword(s):  
Stem Cells ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Point Mutations ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Tyrosine Kinase Activity ◽  
Abl Kinase ◽  
Kinase Domain Mutations

Abstract Growing evidence indicates that the therapeutic potential of imatinib mesylate (IM) for the treatment of CML may be limited initially by a relative innate resistance of the leukemic stem cells and eventually by an accumulation of cells with BCR-ABL tyrosine kinase domain mutations. We now show that the amount and tyrosine kinase activity of p210-BCR-ABL in the most primitive and relatively IM-unresponsive lin−CD34+CD38− CML cells is 3 to 10-fold higher than in the majority of the lin−CD34+CD38+ CML progenitors (n=3). These results confirm previous BCR-ABL transcript data and identify elevated p210-BCR-ABL expression to be a likely important factor in the characteristic IM-insensitivity of very primitive CML cells. To determine whether in vivo, CML stem cells also accumulate gene mutations affecting the BCR-ABL kinase domain, cDNAs were prepared from RNA extracts of purified lin−CD34+CD38− cells isolated from 3 chronic phase patients that had not received IM therapy. Bidirectional sequencing of individually cloned cDNAs from these samples revealed BCR-ABL kinase domain mutations in 2 of the 3 patients at frequencies of 10% (1/10), 20% (2*/10,*identical mutations). Incubation of these lin−CD34+CD38− cells in vitro for 2–3 wk ± a high concentration of IM (up to 10 μM, which was sufficient to reduce the tyrosine kinase activity in the input cells by 70±12% and in their 2 wk progeny by 10±5%) selected a subpopulation of more differentiated and completely IM-resistant cells. This was shown in Western blots by the inability of 10 μM IM to reduce either their p210-BCR-ABL tyrosine kinase activity or CrkL phosphorylation and in methylcellulose assays ±5 μM IM. As predicted, IM-selected cells showed a higher frequency of kinase domain mutations (13–20% vs 0–20% of cDNA clones analyzed from 3 wk cells cultured ±IM). Analysis of individual colonies produced from CFCs in the cultured cells showed all (21/21) colonies from IM-selected cells had mutations vs 50% (5/10) in those cultured without IM. The total frequency of mutant cDNAs detected was also increased in the IM-resistant cells (35–55% vs 10–25% mutant cDNAs in selected vs control cells). Interestingly, in most cases, both wild-type and mutant cDNAs were identified in the same colony, indicating de novo generation of mutations in vitro. Overall, >50 different mutations were identified. These included 10 point mutations previously associated with clinical IM resistance (including G250 and T315), another 13 point mutations previously identified in a comprehensive mutational screen, and >20 previously undescribed mutations. Several of the latter affect the critical region of the P loop, the c-helix and the activation loop and would be predicted to confer significant IM resistance. To investigate the possibility that the observed genomic instability of very primitive CML cells might be related to their elevated innate p210-BCR-ABL activity, BCR-ABL transcript levels in individual IM-selected, fully resistant and control (similarly treated but no IM exposure) colonies were compared. This showed that BCR-ABL transcripts were ~20-fold higher (P<0.05) in the resistant colonies (30 assessed from 3 patients). These findings suggest that the increased BCR-ABL expression and activity that uniquely characterizes the most primitive CML cells may contribute not only to their innate insensitivity to IM but also to a deregulation of genomic stability leading to the emergence of IM-resistant mutants and other subclones associated with disease progression.

scholarly journals Interaction of activated Cdc42-associated tyrosine kinase ACK2 with HSP90

2004 ◽  
Vol 382 (1) ◽  
pp. 199-204 ◽  
Author(s):  
Wannian YANG ◽  
Jaclyn M. JANSEN ◽  
Qiong LIN ◽  
Sabrina CANOVA ◽  
Richard A. CERIONE ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Heat Shock Protein 90 ◽  
Kinase Domain ◽  
Atpase Inhibitor ◽  
Sorting Nexin ◽  
Downstream Effector ◽  
Tyrosine Kinase 2 ◽  
Functional Complex

ACK2 (activated Cdc42-associated tyrosine kinase 2) is a specific downstream effector for Cdc42, a member of the Rho family of small G-proteins. ACK2 interacts with clathrin, an endocytic vesicle coating protein, and SH3PX1, a sorting nexin, and is involved in clathrin-mediated endocytosis. While searching for proteins that interact with ACK2, we found that HSP90 (heat-shock protein 90) binds to ACK2. Analysis of a series of truncation mutants of ACK2 has defined the regions within the kinase domain of ACK2 that are required for binding to HSP90. The binding of HSP90 to ACK2 is blocked upon treatment with geldanamycin, an HSP90-specific ATPase inhibitor, and is required for the in vivo kinase activity of ACK2 and its association with Cdc42. Overall, our data suggest a novel mechanism of regulation in which HSP90 serves as a regulatory component in an ACK2 functional complex and plays a role in sustaining its kinase activity.

scholarly journals RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization

2019 ◽  
Vol 116 (47) ◽  
pp. 23705-23713 ◽  
Author(s):  
Takashi Ueta ◽  
Kenji Ishihara ◽  
Shoji Notomi ◽  
Jong-Jer Lee ◽  
Daniel E. Maidana ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Inflammatory Cells ◽  
Corneal Neovascularization ◽  
Inhibitory Effect ◽  
Interleukin 4 ◽  
Caspase Activation ◽  
Interacting Protein ◽  
Pathological Angiogenesis ◽  
Caspase Inhibition

Inflammation plays an important role in pathological angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation; however, a comprehensive description of its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1K45A/K45A mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization, Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis is mediated by caspase activation through a kinase-independent function of RIP1 and RIP3. Mechanistically, infiltrating macrophages are the key target of RIP1 kinase inhibition to attenuate pathological angiogenesis. Inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of proangiogenic M2-like markers but not M1-like markers. Similarly, in vitro, catalytic inhibition of RIP1 down-regulates the expression of M2-like markers in interleukin-4–activated bone marrow-derived macrophages, and this effect is blocked by simultaneous caspase inhibition. Collectively, these results demonstrate a nonnecrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may be a therapeutic target of pathological angiogenesis.

Proline-Rich Tyrosine Kinase-2 (PYK2): A New Target for the Treatment of Hematopoietic Neoplasms with TEL-FGFR3 Fusion or FGFR3 Active Mutation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3360-3360
Author(s):  
Daisuke Okamura ◽  
Fumiharu Yagasaki ◽  
Tomoya Maeda ◽  
Maho Ishikawa ◽  
Itsuro Jinnai ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Myeloma Cell ◽  
Kinase Assay ◽  
G1 Arrest ◽  
Dependent Manner ◽  
Tyrosine Kinase 2

Abstract Constitutive activation of Fibroblast Growth Factor 3 (FGFR3) tyrosine kinase have been identified in various human cancers and have been reported to play an important role in some hematopoietic neoplasms. We have previously reported that TEL-FGFR3 in a patient with peripheral T-cell Lymphoma and AML conferred IL-3 independency to Ba/F3 cells and activates PLCγ, PK3K, STAT3, STAT5, MAPK through its constitutive tyrosine kinase activity in TEL-FGFR3 transfected Ba/F3 cells (TF-V5). In KMS-11, human multiple myeloma cell line which expresses constitutively active mutant FGFR3, activations of PI3K and STAT3 pathways have been reported. However, little is known about how FGFR3 tyrosine kinase (TK) activates these downstream molecules. Here, we show that PYK2, a member of focal adhesion kinases, plays a pivotal role for the activation of PI3K, STAT3 and STAT5 in FGFR3 oncogenic pathways, and is a candidate for therapeutic target. PP1/PP2, a kinase inhibitor of SRC and PYK2, inhibited the cell growth of TF-V5 and KMS-11 cells in a dose-dependent manner (IC50=15μM, 25μM respectively), not affecting the cell growth of IL-3 dependent Ba/F3 cells. Another specific SRC inhibitor did not affect the cell growth of TF-V5 and KMS-11 cells. TEL-FGFR3 transfection to Ba/F3 cells led to the overexpression of PYK2 but not FAK. Expression and phosphorylation of PYK2 were identified in KMS-11 cells. Immunoprecipitation analysis using FGFR3 TK inhibitor SU5402 showed that the activation of PYK2 which was recruited to FGFR3 was dependent on the kinase activity of FGFR3. The cell growth of TF-V5 was completely inhibited at the concentration of PP1/PP2(30μM), which inhibited auto-phosphorylation of PYK2. PP1/PP2 suppressed the activation of PI3K-ATK pathway and decreased expression of C-MYC, inducing G1-arrest of TF-V5. PP1/PP2 induced intrinsic apoptosis of TF-V5 and did not affect activation of BAX but decrease expression of BCL-2 and BCL-XL through inactivation of STAT3 and STAT5. PP1/PP2 also inhibited the activation of PI3K and STAT3 in KMS-11 cells, inducing G1-arrest and apoptosis. PP1/PP2 inhibited tyrosine kinase of PYK2 mesured by in vitro kinase assay (IC50=23μM, 13μM, respectively). Further PYK2 C-terminus Associated Protein (PAP) siRNA expression plasmid significantly decreased the proliferation of TF-V5 but not mock transfected Ba/F3 cells. Our data demonstrates that PYK2 is an attractive molecular target for FGFR3 associated hematopoietic neoplasm.

scholarly journals CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis

2020 ◽  
Vol 117 (4) ◽  
pp. 1962-1970 ◽  
Author(s):  
Sarah Hanna-Addams ◽  
Shuzhen Liu ◽  
Hua Liu ◽  
She Chen ◽  
Zhigao Wang
Keyword(s):  
Kinase Activity ◽  
Kinase Domain ◽  
Necrotic Cell ◽  
Interacting Protein ◽  
Casein Kinase 1 ◽  
Mixed Lineage Kinase ◽  
Recognition Motif ◽  
Cell Death Pathway

Necroptosis is a regulated necrotic cell death pathway, mediated by a supermolecular complex called the necrosome, which contains receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). Phosphorylation of human RIPK3 at serine 227 (S227) has been shown to be required for downstream MLKL binding and necroptosis progression. Tandem immunoprecipitation of RIPK3 reveals that casein kinase 1 (CK1) family proteins associate with the necrosome upon necroptosis induction, and this interaction depends on the kinase activity of RIPK3. In addition, CK1 proteins colocalize with RIPK3 puncta during necroptosis. Importantly, CK1 proteins directly phosphorylate RIPK3 at S227 in vitro and in vivo. Loss of CK1 proteins abolishes S227 phosphorylation and blocks necroptosis. Furthermore, a RIPK3 mutant with mutations in the CK1 recognition motif fails to be phosphorylated at S227, does not bind or phosphorylate MLKL, and is unable to activate necroptosis. These results strongly suggest that CK1 proteins are necrosome components which are responsible for RIPK3-S227 phosphorylation.

scholarly journals Physical and Functional Interaction of Growth Hormone and Insulin-Like Growth Factor-I Signaling Elements

2004 ◽  
Vol 18 (6) ◽  
pp. 1471-1485 ◽  
Author(s):  
Yao Huang ◽  
Sung-Oh Kim ◽  
Ning Yang ◽  
Jing Jiang ◽  
Stuart J. Frank
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Janus Kinase ◽  
Intact Cells ◽  
Igf I

Abstract GH and IGF-I are critical regulators of growth and metabolism. GH interacts with the GH receptor (GHR), a cytokine superfamily receptor, to activate the cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2), and initiate intracellular signaling cascades. IGF-I, produced in part in response to GH, binds to the heterotetrameric IGF-I receptor (IGF-IR), which is an intrinsic tyrosine kinase growth factor receptor that triggers proliferation, antiapoptosis, and other biological actions. Previous in vitro and overexpression studies have suggested that JAKs may interact with IGF-IR and that IGF-I stimulation may activate JAKs. In this study, we explore interactions between GHR-JAK2 and IGF-IR signaling pathway elements utilizing the GH and IGF-I-responsive 3T3-F442A and 3T3-L1 preadipocyte cell lines, which endogenously express both the GHR and IGF-IR. We find that GH induces formation of a complex that includes GHR, JAK2, and IGF-IR in these preadipocytes. The assembly of this complex in intact cells is rapid, GH concentration dependent, and can be prevented by a GH antagonist, G120K. However, it is not inhibited by the kinase inhibitor, staurosporine, which markedly inhibits GHR tyrosine phosphorylation. Moreover, complex formation does not appear dependent on GH-induced activation of the ERK or phosphatidylinositol 3-kinase signaling pathways or on the tyrosine phosphorylation of GHR, JAK2, or IGF-IR. These results suggest that GH-induced formation of the GHR-JAK2-IGF-IR complex is governed instead by GH-dependent conformational change(s) in the GHR and/or JAK2. We further demonstrate that GH and IGF-I can synergize in acute aspects of signaling and that IGF-I enhances GH-induced assembly of conformationally active GHRs. These findings suggest the existence of previously unappreciated relationships between these two hormones.

The Bcr-Abl SH2-Kinase Domain Interface Is Critical for Leukemogenesis and An Additional Therapeutic Target in CML.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 37-37
Author(s):  
Oliver D. Hantschel ◽  
Florian Grebien ◽  
Ines Kaupe ◽  
Boris Kovacic ◽  
John Wojcik ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Kinase Activity ◽  
Critical Factor ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Wild Type ◽  
Tyrosine Kinase Activity ◽  
Downstream Signaling

Abstract Abstract 37 We previously showed that the Abl SH2 domain is an allosteric activator of c-Abl tyrosine kinase activity and substrate phosphorylation (Filippakopoulos et al. (2008) Cell 134(5), 793-803). This effect is exerted directly by docking of the SH2 domain onto the N-lobe of the kinase domain in the active conformation of c-Abl. We also showed that the same structural mechanism is a critical factor for full activation of the oncogenic fusion kinase Bcr-Abl. Disruption of binding of the SH2 domain to the kinase domain in Bcr-Abl by the Ile164Glu mutation in the SH2 domain, led to a strong reduction in in vitro tyrosine kinase activity and Bcr-Abl autophosphorylation. Unexpectedly, we observed a differential attenuation of downstream signaling pathways upon disruption of the SH2-kinase domain interface, indicating different activation thresholds of Bcr-Abl downstream signaling pathways. Here, we show that disrupting the SH2-kinase domain interface abrogates the transforming capacity of Bcr-Abl. Cells expressing the Bcr-Abl Ile164Glu mutant were unable to generate cytokine-independent colonies in vitro. Furthermore, mice transplanted with Bcr-Abl Ile164Glu expressing bone marrow cells did not develop the characteristic MPD-like disease that is caused by wild-type Bcr-Abl. Mice that received Bcr-Abl Ile164Glu cells showed normal survival, blood counts and histology after more than 100 days post-transplant, despite the presence of Bcr-Abl Ile164Glu-expressing cells in all blood lineages. This shows that the formation of the SH2-kinase domain interface is strictly necessary for Bcr-Abl to cause CML. Together with our data that show sensitization to imatinib inhibition of Bcr-Abl Ile164Glu as compared to Bcr-Abl wild-type, this argues for the SH2-kinase domain interface as an additional drug target on Bcr-Abl that may synergize with tyrosine kinase inhibitors and may be useful to inhibit tyrosine kinase inhibitor resistant Bcr-Abl clones. To address possibilities to interfere with the SH2-kinase domain interface, we are using an engineered binding protein that binds to the Abl SH2 domain with high-affinity and specificity and supposedly disrupts the interface with the kinase domain, resulting in a decrease in Bcr-Abl kinase activity. In conclusion, we provide strong evidence that the structural positioning of the SH2 domain is a crucial factor for constitutive activity, signal transduction and leukemogenicity of Bcr-Abl. Besides oligomerization via the N-terminal coiled-coiled domain and loss of the auto-inhibitory N-terminal myristoyl group, the proper positioning of the SH2 domain appears to be another critical factor that is required for constitutive activation of Bcr-Abl. Inhibitors of the SH2-kinase domain interface of Bcr-Abl may comprise alternative or additional points of pharmacological intervention for the treatment of imatinib-sensitive or -resistant CML or Ph+ acute lymphocytic leukemia. Disclosures: No relevant conflicts of interest to declare.

NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3948-3954 ◽  
Author(s):  
Shinya Kimura ◽  
Haruna Naito ◽  
Hidekazu Segawa ◽  
Junya Kuroda ◽  
Takeshi Yuasa ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Inhibitory Effect ◽  
Kinase Domain ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase ◽  
Imatinib Resistant ◽  
Novel Agent

Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region–Abl (Bcr-Abl)–positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl–bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.

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