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GZD856 formic is a potent and orally active PDGFRα/β inhibitor, with IC50s of 68.6 and 136.6 nM, respectively. GZD856 formic is also a Bcr-AblT315I inhibitor, with IC50s of 19.9 and 15.4 nM for native Bcr-Abl and the T315I mutant. GZD856 formic has antitumor activity[1][2]. GZD856 (formic) is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups. | [in vivo]
GZD856 (10-30 mg/kg, p.o. once daily for 16 d) displays good antitumor activity in both H1703 and A549 lung cancer models and is well tolerated. GZD856 inhibits brain and liver metastasis of lung cancer cells in an A549-Luc orthotopic model[1].
GZD856 (10 mg/kg; p.o. once daily for 8 d) potently inhibits tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-AblT315I[2].
GZD856 (5 mg/kg; a single i.v.) exhibits a long half-life (T1/2=19.97 h), optimal plasma exposure (Cmax=934.38 μg/L) and a AUC0-∞ (8165.8 μg/L h) in rats[1].
GZD856 (25 mg/kg; a single p.o.) exhibits a long half-life (T1/2=22.2 h), optimal plasma exposure (Cmax=899.5 μg/L) and a good oral bioavailability (BA=78%) in rats[1]. | Animal Model: | Male CB17-SCID mice implanted with H1703 and A549 cancer cells[1] | | Dosage: | 10, 30 mg/kg | | Administration: | Oral gavage once daily for 16 days | | Result: | Displayed antitumor effects in H1703-xenograft mice, with tumor growth inhibition (TGI) values of 20.8% and 74.1% at dosages of 10 and 30 mg/kg, respectively.
Displayed antitumor effects in A549-xenograft mice, with a TGI value of 51.1% at 30 mg/kg.
Was well tolerated in all of the tested groups, with no mortality or significant loss of body weight. |
| Animal Model: | Sprague-Dawley (SD) rats (180-220?g)[1] | | Dosage: | 5 mg/kg for i.v.; 25 mg/kg for p.o. (Pharmacokinetic Analysis) | | Administration: | A single intravenous injection and oral administration | | Result: | I.v.: T1/2=19.97 h; Cmax=934.38 μg/L; AUC0-∞=8165.8 μg/L?h.
P.o.: T1/2=22.2 h; Cmax=899.5 μg/L; BA=78%. |
| [IC 50]
PDGFRα: 68.6 nM (IC50); PDGFRβ: 136.6 nM (IC50); Bcr-AblT315I: 15.4 nM (IC50); Bcr-Abl: 19.9 nM (IC50) | [References]
[1] Zhang Z, et, al. GZD856, a novel potent PDGFRα/β inhibitor, suppresses the growth and migration of lung cancer cells in vitro and in vivo. Cancer Lett. 2016 May 28;375(1):172-178. DOI:10.1016/j.canlet.2016.02.017
[2] Lu X, et, al. Synthesis and identification of GZD856 as an orally bioavailable Bcr-Abl T315I inhibitor overcoming acquired imatinib resistance. J Enzyme Inhib Med Chem. 2017 Dec;32(1):331-336. DOI:10.1080/14756366.2016.1250757 |
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