Identification of 4-Aminopyrazolylpyrimidines as Potent Inhibitors of Trk Kinases

Wang, Tao; Lamb, Michelle L.; Scott, David A.; Wang, Haixia; Block, Michael H.; Lyne, Paul; Lee, John W.; Davies, Audrey M.; Zhang, Haijun; Zhu, Yanyi; Gu, Fei; Han, Yongxin; Wang, Bin; Mohr, Peter J.; Kaus, Robert; Josey, John A.; Hoffmann, Ethan; Thress, Ken; Macintyre, Terry; Wang, Haiyun; Omer, Charles A.; Yu, Dingli

doi:10.1021/jm800343j

Cited by 73 publications

(73 citation statements)

References 33 publications

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“…30 AZD7451 was found to inhibit the in vitro activity of all three Trk isoforms, with an IC 50 ¼ 0.2 nM for TrkA in cells and inhibition of phosphorylation of TrkB and TrkC at p3 nM. AZD7451 also exhibits slow-off rate kinetics for Trk kinases, suggesting for increased residence time on the target.…”

Section: Azd7451mentioning

confidence: 96%

“…In this cell model that easily tolerated high TrkC expression and allowed studying TrkC signaling with and without its ligand, addition of NT-3 triggered rapid and marked TrkC Tyr-phosphorylation, which could be completely blocked by a small-molecule pan-Trk inhibitor, AZD7451. 30 Without NT-3, TrkC remained unphosphorylated ( Figure 3a and Supplementary Figure 2).…”

Section: Introductionmentioning

confidence: 99%

“…We further show that NT-3-induced TrkC phosphorylation and pro-invasive cell behavior was effectively blocked by sub-micromolar concentrations of AZD7451, a small molecule pan-Trk inhibitor. 30 RESULTS ACC gene expression signature identifies expression of neurologic stem cell markers and elements of the Wnt and Notch pathways Gene expression profiles for human salivary ACC (n ¼ 7) was compared with profiles of salivary mucoepidermoid carcinoma (MEC, n ¼ 6), salivary adenocarcinoma (AD, n ¼ 2) and head and neck squamous cell carcinoma (HNSCC) (n ¼ 10) collected at the time of biopsy or resection at our institution (Table 1). Expression array analyses identified genes whose expression discriminate ACC, MEC and HNSCC.…”

Section: Introductionmentioning

confidence: 99%

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TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

et al. 2012

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Treatment options for adenoid cystic carcinoma (ACC) of the salivary gland, a slowly growing tumor with propensity for neuroinvasion and late recurrence, are limited to surgery and radiotherapy. Based on expression analysis performed on clinical specimens of salivary cancers, we identified in ACC expression of the neurotrophin-3 receptor TrkC/NTRK3, neural crest marker SOX10, and other neurologic genes. Here, we characterize TrkC as a novel ACC marker, which was highly expressed in 17 out of 18 ACC primary-tumor specimens, but not in mucoepidermoid salivary carcinomas or head and neck squamous cell carcinoma. Expression of the TrkC ligand NT-3 and Tyr-phosphorylation of TrkC detected in our study suggested the existence of an autocrine signaling loop in ACC with potential therapeutic significance. NT-3 stimulation of U2OS cells with ectopic TrkC expression triggered TrkC phosphorylation and resulted in Ras, Erk 1/2 and Akt activation, as well as VEGFR1 phosphorylation. Without NT-3, TrkC remained unphosphorylated, stimulated accumulation of phospho-p53 and had opposite effects on p-Akt and p-Erk 1/2. NT-3 promoted motility, migration, invasion, soft-agar colony growth and cytoskeleton restructuring in TrkC-expressing U2OS cells. Immunohistochemical analysis demonstrated that TrkC-positive ACC specimens also show high expression of Bcl2, a Trk target regulated via Erk 1/2, in agreement with activation of the TrkC pathway in real tumors. In normal salivary gland tissue, both TrkC and Bcl2 were expressed in myoepithelial cells, suggesting a principal role for this cell lineage in the ACC origin and progression. Sub-micromolar concentrations of a novel potent Trk inhibitor AZD7451 completely blocked TrkC activation and associated tumorigenic behaviors. Pre-clinical studies on ACC tumors engrafted in mice showed efficacy and low toxicity of AZD7451, validating our in vitro data and stimulating more research into its clinical application. In summary, we describe in ACC a previously unrecognized pro-survival neurotrophin signaling pathway and link it with cancer progression.

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Section: Azd7451mentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

et al. 2012

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“…11 We have previously reported compound 1a (AZ-23) that showed potent TrkA/B inhibitory activities in vitro and in vivo and possessed good physical and pharmacokinetic properties. 12,13 Treatment with 1a inhibited the growth of human neuroblastoma xenograft tumors, and its combination with topotecan resulted in the prolonged inhibition of tumor regrowth.…”

mentioning

confidence: 99%

Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors

Wang

Lamb

Block

et al. 2012

ACS Med. Chem. Lett.

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Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.

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“…1A; ref. 33). Kinetic analysis of TrkA kinase activity in the presence of varied concentrations of both ATP and compound (Fig.…”

Section: Identification Of Novel Small-molecule Trk Kinase Inhibitorsmentioning

confidence: 99%

Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway

Thress

Macintyre

Wang

et al. 2009

Molecular Cancer Therapeutics

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Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine kinases that, along with their ligands, the neurotrophins, are involved in neuronal cell growth, development, and survival. The Trk-neurotrophin pathway may also play a role in tumorigenesis through oncogenic fusions, mutations, and autocrine signaling, prompting the development of novel Trk inhibitors as agents for cancer therapy. This report describes the identification of AZ-23, a novel, potent, and selective Trk kinase inhibitor. In vitro studies with AZ-23 showed improved selectivity over previous compounds and inhibition of Trk kinase activity in cells at low nanomolar concentrations. AZ-23 showed in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma. AZ-23 represents a potent and selective Trk kinase inhibitor from a novel series with the potential for use as a treatment for cancer.

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Identification of 4-Aminopyrazolylpyrimidines as Potent Inhibitors of Trk Kinases

Cited by 73 publications

References 33 publications

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

Discovery of Disubstituted Imidazo[4,5-b]pyridines and Purines as Potent TrkA Inhibitors

Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway

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