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

Thress, Kenneth S.; Macintyre, Terry; Wang, Haiyun; Whitston, Dave; Liu, Zhong Ying; Hoffmann, Ethan; Wang, Tao; Brown, Jeffrey L.; Webster, Kevin R.; Omer, Charles A.; Zage, Peter E.; Zeng, Lizhi; Zweidler‐McKay, Patrick A.

doi:10.1158/1535-7163.mct-09-0036

Cited by 55 publications

(55 citation statements)

References 38 publications

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“…Compound 1a had been tested in an earlier version of this assay panel (177 kinases) at 0.5 μM concentration; of kinases inhibited by >75% in this screen, dose−response curves for TrkA, TrkB, FGFR1, Flt3, Ret, MuSK, and Lck resulted in IC 50 values less than 100 nM. 13 While it is challenging to compare the data for 2c to the historical data for its matched pair across differing panel, concentration, and selection criteria, considering the metric of number of (non-Trk) kinases with IC 50 less than 100 nM, it appears the chlorine atom at the hinge in 1a may confer additional selectivity over 2c. However, from a cellular perspective, the effect of 1a on proliferation in MCF10A-TrkA-Δ (1.51 nM) and MCF10A parental cells (2430 nM) was previously reported, with >1600-fold selectivity resulting when signaling is driven through TrkA.…”

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confidence: 99%

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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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Section: %mentioning

confidence: 99%

“…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.…”

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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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“…Indeed, they may also inhibit other tyrosine kinases, such as Flt3 or RET [54,55]. Increased pharmaceutical interest on Trk inhibitors leads to the development of a highly selective pan-Trk inhibitor, AZ-23 (AstraZeneca R&D, Boston, MA) with low nM selectivity and good antitumor activity (against neuroblastoma) [56]. Very recently, Cazorla et al have developed the first highly potent anxiolytic small peptide TrkB inhibitor-Cyclotraxin-B [57].…”

Section: Discussionmentioning

confidence: 99%

K252a induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr Virus (EBV)—associated nasopharyngeal carcinoma cells

Wong

Lau

et al. 2010

Invest New Drugs

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Recent studies revealed an unexpected role of the neurotrophin receptor pathway, BDNF/TrkB signaling, in cancer metastasis and anoikis (i.e. detachment-induced cell death). Survival of cancer cells in detached state (known as anoikis-resistance) is known to be pre-requisite for metastasis. Nasopharyngeal carcinoma (NPC), an endemic head and neck cancer in Southeast Asia, is highly invasive, metastatic, and etiologically associated with Epstein-Barr virus (EBV, an oncovirus) infection. Mechanistic studies on the invasive/metastatic nature of NPC can facilitate the development of anti-metastatic therapy in NPC. Thus far, the role of BDNF/TrkB signaling in virus-associated human cancer is unclear. Here, using multiple cell line models of NPC with EBV-association (HONE-1-EBV, HK1-LMP1 and C666-1), we investigated the potential involvement of BDNF/TrkB signaling in cellular migration and anoikis-resistant characteristics of NPC. We found that all three EBV-associated NPC cell lines tested were intrinsically anoikis-resistant (i.e. survived in detached state) and expressed both BDNF and TrkB. BDNF stimulation induced cellular migration, but not proliferation of these cells. Further, we examined if pharmacologic targeting of anoikis-resistance of NPC cells can be achievable by a proof-of-concept Trk inhibitor, K252a, in these EBV-associated NPC models. Our results demonstrated that K252a, was able to attenuate BDNF-induced migration and proliferation of NPC cells. More importantly, we demonstrated for the first time that K252a harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced cell death) against EBV-associated human cancer cells, namely NPC cells. This proof-of-concept study demonstrated that K252a, a Trk inhibitor, can potentially be used as an anoikis-sensitizing agent in NPC.

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“…A dose of 20 mg/kg delivered daily for 3 weeks was chosen based on existing pre-clinical data; 25 there was no existing data combining AZD1332 with radiation. Figure 5 shows that there was a very minimal effect of the drug alone on the growth of MIA-PaCa-2 xenografts but unequivocally no interaction with radiation in vivo.…”

Section: Does a Specific Trk Inhibitor Increase The Effect Of Radiatimentioning

confidence: 99%

The significance of Trk receptors in pancreatic cancer

et al. 2017

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This study investigated the Trk receptor family as a therapeutic target in pancreatic ductal adenocarcinoma and assessed their prognostic significance. Global gene expression analysis was investigated in prospectively collected pancreatic ductal adenocarcinomas that had either undergone neoadjuvant chemoradiation or were treated by surgery. PANC-1 and MIA-PaCa-2 cell lines were investigated to establish whether fractionated radiation altered expression of four neuroendocrine genes and whether this resulted in subsequent changes in radiosensitivity. A specific inhibitor of TrkA, B, and C, AstraZeneca 1332, was investigated in vitro and in vivo in combination with radiation. A tissue microarray was constructed from 77 pancreatic ductal adenocarcinoma patients who had undergone neoadjuvant chemoradiation and the Trk receptor, and neurogenic differentiation 1 expression was assessed and correlated with overall survival. A total of 99 genes were identified that were differentially expressed in the chemoradiation patients with neuroendocrine genes and pathways, in particular the neurogenic differentiation 1 and Trk receptor family, being prominent. Fractionated radiation upregulated the expression of neuroendocrine genes, and AstraZeneca 1332 treatment in vitro enhanced radiosensitivity. No added effect of AstraZeneca 1332 was observed in vivo. Trk receptor expression varied between isoforms but did not correlate significantly with clinical outcome. Radiation treatment upregulated neuroendocrine gene expression but the Trk receptor family does not appear to be a promising treatment target.

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

Cited by 55 publications

References 38 publications

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

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

K252a induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr Virus (EBV)—associated nasopharyngeal carcinoma cells

The significance of Trk receptors in pancreatic cancer

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