Discovery of a Potent Inhibitor of Anaplastic Lymphoma Kinase with in Vivo Antitumor Activity

Ott, Gregory R.; Tripathy, Rabindranath; Cheng, Mangeng; McHugh, Robert J.; Anzalone, Andrew V.; Underiner, Ted L.; Curry, Matthew A; Quail, Matthew R.; Lü, Lihui; Wan, Wei; Angeles, Thelma S.; Albom, Mark S.; Aimone, Lisa D.; Ator, Mark A.; Ruggeri, Bruce; Dorsey, Bruce D.

doi:10.1021/ml100158s

Cited by 42 publications

(40 citation statements)

References 20 publications

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“…To differentiate these prospective candidates, single dose (30 mg/kg, po) PK/PD studies in ALKdriven subcutaneous tumor xenografts (SUP-M2) were performed. Prior studies with small-molecule ATP-competitive inhibitors, both internal 33 and externally reported, 12 demonstrated (27,30, and 32) demonstrated sufficient target inhibition in vivo (>75% over 6À12 h) to be evaluated in chronic dosing antitumor studies. Upon the basis of the PK/PD data, with bid dosing at 30 mg/kg and higher, antitumor responses should be effected with 27, 30, and 32.…”

Section: ' Results and Discussionmentioning

confidence: 99%

2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity

Ott¹,

Wells²,

Thieu³

et al. 2011

J. Med. Chem.

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A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.

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Section: ' Results and Discussionmentioning

confidence: 99%

2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity

Ott¹,

Wells²,

Thieu³

et al. 2011

J. Med. Chem.

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“…In order to determine whether serine phosphorylation of GSK3β is NPM-ALK dependent, we utilized a small molecule (Compound 15) to inhibit ALK kinase (Ott et al , 2010). Treatment of SU-DHL-1 cells with the ALK inhibitor for 2 and 6 h resulted in a marked decrease in the levels of phosphorylated NPM-ALK (Y1604), but not total NPM-ALK (Figure 1c).…”

Section: Resultsmentioning

confidence: 99%

NPM-ALK signals through glycogen synthase kinase 3β to promote oncogenesis

et al. 2011

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Anaplastic large cell lymphoma (ALCL) is the most common type of pediatric peripheral T-cell lymphoma. In 70–80% of cases, the chromosomal aberration t(2;5)(p23;q35) results in the juxtaposition of anaplastic lymphoma kinase (ALK) with nucleophosmin (NPM) and the subsequent expression of the NPM-ALK fusion protein. NPM-ALK is a chimeric tyrosine kinase, which induces numerous signaling pathways that drive proliferation and abrogate apoptosis. However, the mechanisms that lead to activation of downstream growth regulatory molecules have not been completely elucidated. Using a mass spectrometry-based phosphoproteomic screen, we identified GSK3β as a signaling mediator of NPM-ALK. Using a selective inhibitor of ALK, we demonstrated that the tyrosine kinase activity of ALK regulates the serine-9 phosphorylation of GSK3β. Expression of NPM-ALK in 293T cells led to an increase of pS9-GSK3β (glycogen synthase kinase 3 beta) compared with kinase-defective K210R mutant NPM-ALK, but did not affect total GSK3β levels. Phosphorylation of pS9-GSK3β by NPM-ALK was mediated by the PI3K/AKT signaling pathway. ALK inhibition resulted in degradation of GSK3β substrates Mcl-1 and CDC25A, which was recovered upon chemical inhibition of the proteasome (MG132). Furthermore, the degradation of Mcl-1 was recoverable with inhibition of GSK3β. ALK inhibition also resulted in decreased cell viability, which was rescued by GSK3β inhibition. Furthermore, stable knockdown of GSK3β conferred resistance to the growth inhibitory effects of ALK inhibition using viability and colony formation assays. pS9-GSK3β and CDC25A were selectively expressed in neoplastic cells of ALK + ALCL tissue biopsies, and showed a significant correlation (P < 0.001). Conversely, ALK-ALCL tissue biopsies did not show significant correlation of pS9-GSK3β and CDC25A expression (P < 0.2). Our results demonstrate that NPM-ALK regulates the phosphorylation of S9-GSK3β by PI3K/AKT. The subsequent inhibition of GSK3β activity results in accumulation of CDC25A and Mcl-1, which confers the advantage of growth and protection from apoptosis. These findings provide support for the role of GSK3β as a mediator of NPM-ALK oncogenesis.

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“…15 Sixhour exposure to CEP was long enough to observe complete abrogation of ALK autophosphorylation at Y1604-ALK in NPM-ALK 1 ALCL cell lines (SU-DHL-1 and SUPM2) but not long enough to significantly impact cell viability (supplemental Figure 1A-B). 15 Phosphoproteomic analysis of SU-DHL-1 revealed that ALK inhibition resulted in the down-regulation of 569 proteins and up-regulation of 102 proteins ( Figure 1B). As expected, the phosphoprotein that changed with greatest significance was ALK (z-score 5 26.0).…”

Section: Phosphoproteomic Analysis Reveals Npm-alk-mediated Phosphorymentioning

confidence: 95%

Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK–mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma

McDonnell¹,

Hwang²,

Rolland³

et al. 2013

Blood

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• NPM-ALK induces a metabolic shift toward biomass production.• NPM-ALK phosphorylates Y105-PKM2 to regulate metabolism and tumorigenesis.The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis. (Blood. 2013;122(6):958-968)

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Discovery of a Potent Inhibitor of Anaplastic Lymphoma Kinase with in Vivo Antitumor Activity

Cited by 42 publications

References 20 publications

2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity

2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity

NPM-ALK signals through glycogen synthase kinase 3β to promote oncogenesis

Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK–mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma

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