RET-IN-16

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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.

For research use only. We do not sell to patients.

RET-IN-16 Chemical Structure

CAS No. : 2259657-48-0

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Description

IC₅₀ & Target

IC₅₀: 3.98 nM (RET(WT)), 8.42 nM (RET(M918T)), 15.05 nM (RET(V804L)), 7.86 nM (RET(V804M)), 5.43 nM (RET-CCDC6), 8.86 nM (RET-KIF5B)^[1]

In Vitro

RET-IN-16 (compound 9x) (0.005-10 μM; 48 hours) exhibits potent activity against CCDC6-RET-Ba/F3 and KIF5B-RET-Ba/F3 with GI₅₀ of 9 nM and 17 nM, respectively^[1].
RET-IN-16 (1 μM; 48 hours) selectively suppresses the proliferation of CCDC6-RET fusion cells^[1].
RET-IN-16 (50 and 100 μM; 4 hours) remarkably blocks the autophosphorylation of RET in KIF5B-RET and KIF5B-RET^V804M Ba/F3 cells, and the phosphorylation of the adapter protein SHC is also inhibited with a dose-dependent manner^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Proliferation Assay

Cell Line:	LC-2/ad, A549, H3122, MDA-MB-231 and A375, SKGT4, HepG2, KYSE450 and BGC823 cells^[1]
Concentration:	1 μM
Incubation Time:	48 hours
Result:	Potently suppressed the proliferation of LC-2/ad NSCLC cells harboring the CCDC6-RET fusion, but dramatically decreased potency against other RET-negative cancer cells.

Western Blot Analysis

Cell Line:	KIF5B-RET and KIF5B-RET^V804M Ba/F3 cells^[1]
Concentration:	50 and 100 μM
Incubation Time:	4 hours
Result:	Remarkably blocked the autophosphorylation of RET, and the phosphorylation of the adapter protein SHC was also inhibited in a dose-dependent manner.

In Vivo

RET-IN-16 (1 mg/kg; IV; single) exhibits a good drug exposure (AUC_0-t = 6959 ± 762 ng·h/mL) and a moderate half-life (T_1/2 = 4.28 ± 0.43 h)^[1].
RET-IN-16 (10 mg/kg; PO; single) exhibits a low maximum plasma concentration (C_max = 194 ± 47 ng·h/mL) and drug exposure (AUC_0-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-RET^V804M in tumor tissues, as well as significantly induces apoptosis in vivo^[1].
Pharmacokinetic Parameters of RET-IN-16 in male Sprague-Dawley rats^[1].

	IV (1 mg/kg)	PO (10 mg/kg)
T_1/2 (h)	4.28 ± 0.43	7.59 ± 1.02
T_max (h)	0.083 ± 0	0.75 ± 0.43
C_max (ng/mL)	6097 ± 623	194 ± 47
AUC_0-t (ng/mL·h)	6959 ± 762	2112 ± 117
AUC_0-∞ (ng/mL·h)	7014 ± 753	2343 ± 157
F (%)		3.0

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

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 (AUC_0-t = 6959 ± 762 ng·h/mL) and a moderate half-life (T_1/2 = 4.28 ± 0.43 h) at 1 mg/kg IV; observed a low maximum plasma concentration (C_max = 194 ± 47 ng·h/mL) and drug exposure (AUC_0-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-RET^V804M in tumor tissues, as well as significantly induced apoptosis in vivo.

Molecular Weight

602.61

Formula

C₃₁H₂₉F₃N₈O₂

CAS No.

2259657-48-0

SMILES

CC1=CC=C(C=C1OC2=C3C=NNC3=NC(C4=CN=CC=C4)=N2)C(NC5=CC(C(F)(F)F)=C(C=C5)CN6CCN(CC6)C)=O

Shipping

Room temperature in continental US; may vary elsewhere.

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Purity & Documentation

Handling Instructions (2659 KB)

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. [Content Brief]

RET-IN-16 Related Classifications

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Help & FAQs

Do most proteins show cross-species activity?
Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

RET-IN-162259657-48-0RETAnticancerWTMutantOralV804MInhibitorinhibitorinhibit

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