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.

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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]

Cellular Effect

Cell Line	Type	Value	Description	References
A-375	GI₅₀	2.947 μM Compound: 9x	Antiproliferative activity against human A-375 cells measured after 48 hrs by MTS assay Antiproliferative activity against human A-375 cells measured after 48 hrs by MTS assay	[PMID: 32882611]
A549	GI₅₀	3.393 μM Compound: 9x	Antiproliferative activity against human A549 cells measured after 48 hrs by MTS assay Antiproliferative activity against human A549 cells measured after 48 hrs by MTS assay	[PMID: 32882611]
BaF3	GI₅₀	8.03 μM Compound: 9x	Cytotoxicity against mouse BaF3 cells assessed as reduction in cell proliferation measured after 48 hrs by MTS assay Cytotoxicity against mouse BaF3 cells assessed as reduction in cell proliferation measured after 48 hrs by MTS assay	[PMID: 32882611]
MDA-MB-231	GI₅₀	2.428 μM Compound: 9x	Antiproliferative activity against human MDA-MB-231 cells measured after 48 hrs by MTS assay Antiproliferative activity against human MDA-MB-231 cells measured after 48 hrs by MTS assay	[PMID: 32882611]
NCI-H3122	GI₅₀	5.679 μM Compound: 9x	Antiproliferative activity against human NCI-H3122 cells measured after 48 hrs by MTS assay Antiproliferative activity against human NCI-H3122 cells measured after 48 hrs by MTS assay	[PMID: 32882611]

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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