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(AZD0530; AZD-0530; AZD 0530)
Saracatinib (AZD0530) is a potent Src inhibitor with IC50 of 2.7 nM, and potent to c-Yes, Fyn, Lyn, Blk, Fgr and Lck; less active for Abl and EGFR (L858R and L861Q).
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Saracatinib (AZD0530) is a highly selective, orally available, dual-specific Src/Abl kinase inhibitor with IC50 of 2.7 and 30 nM for c-Src and Abl kinase, respectively.
1 . Fujisaka Y, Onozawa Y, Kurata T, Yasui H, Goto I, Yamazaki K, Machida N, Watanabe J, Shimada H, Shi X, Boku N.First report of the safety, tolerability, and pharmacokinetics of the Src kinase inhibitor saracatinib (AZD0530) in Japanese patients with advanced solid tumours.Invest New Drugs. 2012 Mar 14.
BACKGROUND: Saracatinib (AZD0530) is a selective, oral Src inhibitor that has demonstrated antitumour activity in preclinical studies. Methods This open-label, dose-escalation, phase I study evaluated the safety and tolerability of saracatinib in Japanese patients with advanced solid tumours (clinicaltrials.gov NCT00704366). Patients received continuous once-daily oral dosing with saracatinib starting 7 days after a single dose in ascending dose cohorts until dose-limiting toxicity (DLT) or disease progression. Pharmacokinetics and efficacy were also evaluated. Results A total of 12 patients received saracatinib at doses of 50 (n?=?3), 125 (n?=?6), and 175 mg (n?=?3). Median durations of exposure were 65, 44, and 16 days in the 50, 125, and 175 mg cohorts, respectively. The most common adverse events were diarrhoea (67?%), nausea (67?%), decreased appetite (58?%), lymphopenia (50?%) and pyrexia (50?%). The most common grade ≥3 adverse events were leukopenia, lymphopenia, neutropenia, and haemoglobin decreased (all 17?%). DLTs occurred in two patients, both in the 175 mg cohort: grade 3 aspartate aminotransferase increased with grade 3 gamma-glutamyltransferase increased (n?=?1); and grade 3 hypoxia (n?=?1). Following a single dose, saracatinib median t(max) across the doses was 2-4 h, and thereafter plasma concentrations declined in a biphasic manner, with mean terminal half-life of approximately 45 h. Geometric mean saracatinib exposures were 0.8-2.1 times greater than those reported in Caucasian patients. The best response was stable disease (50 mg, n?=?2; 125 mg, n?=?1). Conclusions Saracatinib was tolerated in Japanese patients with advanced solid tumours at doses up to 125 mg.
2 . Cavalloni G, Peraldo-Neia C, Sarotto I, Gammaitoni L, Migliardi G, Soster M, Marchiò S, Aglietta M, Leone F.Antitumor activity of Src inhibitor saracatinib (AZD-0530) in preclinical models of biliary tract carcinomas.Mol Cancer Ther. 2012 Jul;11(7):1528-38. Epub 2012 Mar 27.
Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is, therefore, an urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the nonreceptor tyrosine kinase Src, observing promising antitumor effects of its small-molecule inhibitor saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from patients with BTC. Upon saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28, and TGBC1-TKB. The effect of saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinib-modulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G(0)-G(1) phase, and inhibited cell migration. At high concentrations (median dose from 2.26-6.99 μmol/L), saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. Here, we provide a demonstration that the targeted inhibition of Src kinase by saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of saracatinib-based clinical applications.
3 . Kaye S, Aamdal S, Jones R, Freyer G, Pujade-Lauraine E, de Vries EG, Barriuso J, Sandhu S, Tan DS, Hartog V, Kuenen B, Ruijter R, Kristensen GB, Nyakas M, Barrett S, Burke W, Pietersma D, Stuart M, Emeribe U, Boven E.Phase I study of saracatinib (AZD0530) in combination with paclitaxel and/or carboplatin in patients with solid tumours.Br J Cancer. 2012 May 22;106(11):1728-34.
BACKGROUND: As a prelude to combination studies aimed at resistance reversal, this dose-escalation/dose-expansion study investigated the selective Src kinase inhibitor saracatinib (AZD0530) in combination with carboplatin and/or paclitaxel. METHODS: Patients with advanced solid tumours received saracatinib once-daily oral tablets in combination with either carboplatin AUC 5 every 3 weeks (q3w), paclitaxel 175 mg m(-2) q3w, paclitaxel 80 mg m(-2) every 1 week (q1w), or carboplatin AUC 5 plus paclitaxel 175 mg m(-2) q3w. The primary endpoint was safety/tolerability...
4 . Liu KJ, He JH, Su XD, Sim HM, Xie JD, Chen XG, Wang F, Liang YJ, Singh S, Sodani K, Talele TT, Ambudkar SV, Chen ZS, Wu HY, Fu LW.Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo.Int J Cancer. 2012 May 24.
Saracatinib, a highly selective, dual Src/Abl kinase inhibitor, is currently in a Phase II clinical trial for the treatment of ovarian cancer. In our study, we investigated the effect of saracatinib on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters in vitro and in vivo. Our results showed that saracatinib significantly enhanced the cytotoxicity of ABCB1 substrate drugs in ABCB1 overexpressing HeLa/v200, MCF-7/adr and HEK293/ABCB1 cells, an effect that was stronger than that of gefitinib, whereas it had no effect on the cytotoxicity of the substrates in ABCC1 overexpressing HL-60/adr cells and its parental sensitive cells. Additionally, saracatinib significantly increased the doxorubicin (Dox) and Rho 123 accumulation in HeLa/v200 and MCF-7/adr cells, whereas it had no effect on HeLa and MCF-7 cells. Furthermore, saracatinib stimulated the ATPase activity and inhibited photolabeling of ABCB1 with [(125) I]-iodoarylazidoprazosin in a concentration-dependent manner. In addition, the homology modeling predicted the binding conformation of saracatinib within the large hydrophobic drug-binding cavity of human ABCB1. However, neither the expression level of ABCB1 nor the phosphorylation level of Akt was altered at the reversal concentrations of saracatinib. Importantly, saracatinib significantly enhanced the effect of paclitaxel against ABCB1-overexpressing HeLa/v200 cancer cell xenografts in nude mice. In conclusion, saracatinib reverses ABCB1-mediated MDR in vitro and in vivo by directly inhibiting ABCB1 transport function, without altering ABCB1 expression or AKT phosphorylation. These findings may be helpful to attenuate the effect of MDR by combining saracatinib with other chemotherapeutic drugs in the clinic. What's new? The overexpression of ATP-binding cassette (ABC) transporters is a common reason for multidrug resistance (MDR) in cancer cells. In this study, saracatinib, a dual Src/Abl tyrosine kinase inhibitor, reversed multidrug resistance mediated by the transporter ABCB1, both in vitro and in vivo. The data indicate that saracatinib, as monotherapy or combination therapy, may be effective in overcoming ABCB1-mediated drug resistance in the clinic.
5 . Hennequin, Laurent F.; Allen, Jack; Breed, Jason; Curwen, Jon; N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a Novel, Highly Selective, Orally Available, Dual-Specific c-Src/Abl Kinase Inhibitor. Journal of Medicinal Chemistry (2006), 49(22), 6465-6488.
Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. We report here a novel subseries of C-5-substituted anilinoquinazolines that display high affinity and specificity for the tyrosine kinase domain of the c-Src and Abl enzymes. These compounds exhibit high selectivity for SFKs over a panel of recombinant protein kinases, excellent pharmacokinetics, and in vivo activity following oral dosing. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-2-(4-methylpiperazin-1-yl)ethoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine (AZD0530) inhibits c-Src and Abl enzymes at low nanomolar concentrations and is highly selective over a range of kinases. ...
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