| Identification | Back Directory | [Name]
Benzamide, 4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[[6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy]- | [CAS]
2259657-48-0 | [Synonyms]
RET-IN-16
Benzamide, 4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[[6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy]- | [Molecular Formula]
C31H29F3N8O2 | [MOL File]
2259657-48-0.mol | [Molecular Weight]
602.61 |
| Hazard Information | Back Directory | [Uses]
RET-IN-16 is a potent and selective RET inhibitor with IC50s of 3.98 nM, 8.42 nM, 15.05 nM, 7.86 nM, 5.43 nM and 8.86 nM for RET(WT), RET(M918T), RET(V804L), RET(V804M), RET-CCDC6 and RET-KIF5B, respectively. RET-IN-16 has anticancer effects[1]. | [in vivo]
RET-IN-16 (1 mg/kg; IV; single) exhibits a good drug exposure (AUC0-t = 6959 ± 762 ng·h/mL) and a moderate half-life (T1/2 = 4.28 ± 0.43 h)[1].
RET-IN-16 (10 mg/kg; PO; single) exhibits a low maximum plasma concentration (Cmax = 194 ± 47 ng·h/mL) and drug exposure (AUC0-t = 2112 ± 117 ng·h/mL)[1].
RET-IN-16 (30 and 50 mg/kg; IV; daily; for 8 days) suppresses tumor growth in a dose-dependent manner, and significantly suppresses p-RET and p-SHC in both KIF5B-RET and KIF5B-RETV804M in tumor tissues, as well as significantly induces apoptosisin vivo[1].
Pharmacokinetic Parameters of RET-IN-16 in male Sprague-Dawley rats[1].
| IV (1 mg/kg) | PO (10 mg/kg) | | T1/2 (h) | 4.28 ± 0.43 | 7.59 ± 1.02 | | Tmax (h) | 0.083 ± 0 | 0.75 ± 0.43 | | Cmax (ng/mL) | 6097 ± 623 | 194 ± 47 | | AUC0-t (ng/mL·h) | 6959 ± 762 | 2112 ± 117 | | AUC0-∞ (ng/mL·h) | 7014 ± 753 | 2343 ± 157 | | F (%) | | 3.0 |
| Animal Model: | Male Sprague-Dawley rats[1] | | Dosage: | 1 mg/kg for IV, 10 mg/kg for PO | | Administration: | IV and PO; single (Pharmacokinetic Analysis) | | Result: | Exhibited a good drug exposure (AUC0-t = 6959 ± 762 ng·h/mL) and a moderate half-life (T1/2 = 4.28 ± 0.43 h) at 1 mg/kg IV; observed a low maximum plasma concentration (Cmax = 194 ± 47 ng·h/mL) and drug exposure (AUC0-t = 2112 ± 117 ng·h/mL) at 10 mg/kg PO. |
| Animal Model: | Half male and female BALB/c-nu mice (6-8 weeks; injected with KIF5B-RET Ba/F3 and KIF5B-RETV804M Ba/F3)[1] | | Dosage: | 30 and 50 mg/kg | | Administration: | IV; daily; for 8 days | | Result: | Suppressed tumor growth in a dose-dependent manner, and significantly suppressed p-RET and p-SHC in both KIF5B-RET and KIF5B-RETV804M in tumor tissues, as well as significantly induced apoptosis in vivo. |
| [References]
[1] Li X, Su J, Yang Y, et al. Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant. Eur J Med Chem. DOI:10.1016/j.ejmech.2020.112755 |
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