PROTAC RET Degrader 1
PROTAC RET Degrader 1 is an orally active, blood-brain barrier-penetrant RET PROTAC degrader with a DC50 of 1.7 nM. PROTAC RET Degrader 1 binds to CRBN and forms a ternary complex with RET, mediating proteasomal degradation of RET, while also selectively mediating the degradation of SALL4. PROTAC RET Degrader 1 inhibits the RET signaling pathway, hERG channel activity, and Cyp3A4 enzyme activity; it suppresses cancer cell growth and induces tumor regression. PROTAC RET Degrader 1 can be used in research related to RET-driven cancers.
(Pink: RET ligand (HY-179308); Blue: Cereblon ligand (HY-179307); Black: linker).
For research use only. We do not sell to patients.
- CAS No.: 2760847-82-1
- Formula: C48H57FN12O3
- Molecular Weight:869.04
-
Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
-
Biological Activity
-
Chemical Information
- Purity & Documentation
- References
-
Help & FAQs
All PROTACs Isoforms
More
Biological Activity
Description
IC50 & Target
[1]|
CYP3A4 |
Cellular Effect
|
Cell Line
|
Type | Value | Description | References |
|---|---|---|---|---|
| HEK-293T | DC50 |
1.7 nM
|
Degradation of wild-type RET kinase domain in HEK293T cells expressing C-terminal HiBiT-tagged wild-type RET kinase domain measured by HiBiT tag readout.
Degradation of wild-type RET kinase domain in HEK293T cells expressing C-terminal HiBiT-tagged wild-type RET kinase domain measured by HiBiT tag readout.
|
40823490 |
| HEK-293T | DC50 |
21 nM
|
Degradation of drug-resistant RET G810R kinase domain in HEK293T cells expressing C-terminal HiBiT-tagged RET G810R kinase domain measured by HiBiT tag readout.
Degradation of drug-resistant RET G810R kinase domain in HEK293T cells expressing C-terminal HiBiT-tagged RET G810R kinase domain measured by HiBiT tag readout.
|
40823490 |
| HEK-293T | DC50 |
3 nM
|
Degradation of drug-resistant RET G810S kinase domain in HEK293T cells expressing C-terminal HiBiT-tagged RET G810S kinase domain measured by HiBiT tag readout.
Degradation of drug-resistant RET G810S kinase domain in HEK293T cells expressing C-terminal HiBiT-tagged RET G810S kinase domain measured by HiBiT tag readout.
|
40823490 |
| HEK-293T | DC50 |
12 nM
|
Degradation of drug-resistant RET G810C kinase domain in HEK293T cells expressing C-terminal HiBiT-tagged RET G810C kinase domain measured by HiBiT tag readout.
Degradation of drug-resistant RET G810C kinase domain in HEK293T cells expressing C-terminal HiBiT-tagged RET G810C kinase domain measured by HiBiT tag readout.
|
40823490 |
In Vitro
PROTAC RET Degrader 1 (compound 20) potently degrades the wild-type RET kinase domain in HEK293T cells, with a DC50 of 1.7 nM and a maximum remaining protein level of 8%; it degrades the drug-resistant RETG810R kinase domain, with a DC50 of 21 nM and a maximum remaining protein rate of 22%; it also degrades the drug-resistant RETG810S and RETG810C kinase domains, with DC50 values of 3 nM and 12 nM, and maximum remaining protein levels of 25% and 31%, respectively[1].
PROTAC RET Degrader 1 binds to CRBN in HEK293T cells, with an IC50 of 10 nM as determined by NanoBRET assay[1].
PROTAC RET Degrader 1 selectively degrades the novel CRBN substrate SALL4 (DC50 = 6.1 μM) in HiBiT-tagged cell lines, without degrading GSPT1 or IKZF1[1].
PROTAC RET Degrader 1 potently inhibits the proliferation of Ba/F3 cells expressing KIF5B-RET fusion proteins carrying drug-resistant mutations (RETG810R, RETV804L, RETY806N, RETL730I)[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
| Species | Dose | Route | CL | T1/2 | Vdss | AUClast | Cmax | Bioavailability |
|---|---|---|---|---|---|---|---|---|
| Mice[1] | 1 mg/kg | i.v. | 18.4 mL/min/kg | 5.3 h | 7.8 L/kg | 814 ng·h/mL | / | / |
| Rat[1] | 1 mg/kg | i.v. | 25.5 mL/min/kg | 8.7 h | 18.2 L/kg | 572 ng·h/mL | / | / |
| Mice[1] | 10 mg/kg | p.o. | / | / | / | 3192 ng·h/mL | 312 ng/mL | 39 % |
| Rat[1] | 10 mg/kg | p.o. | / | / | / | 475 ng·h/mL | 35.4 ng/mL | 8 % |
In Vivo
PROTAC RET Degrader 1 (30 mg/kg; p.o.; single administration) can cross the blood-brain barrier, accumulate in intracranial colorectal cancer PDX tumors driven by the CCDC6-RET fusion, and induce rapid and potent RET degradation as well as pathway inhibition[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
-
Animal Model:BALB/c mice received subcutaneous implantation of tumor fragments of RET‑driven NSCLC bearing the KIF5B‑RET fusion (CTG‑0838)[1]
-
Dosage:5 mg/kg (i.v.); 30 mg/kg (p.o.)
-
Administration:i.v.; QD
p.o.; QD -
Result:Achieved tumor regression comparable to Selpercatinib.
Reduced KIF5B-RET protein levels by >50% within 5 hours after single administration.
Retained robust reduction in pSHC at 24 hours after single administration.
Produced sustained degradation of KIF5B-RET with repeated dosing.
-
Animal Model:BALB/c mice received subcutaneous implantation of tumor fragments of colorectal cancer bearing the CCDC6‑RET fusion (CR2518)[1]
-
Dosage:5 mg/kg (i.v.); 30 mg/kg (p.o.)
-
Administration:i.v.; QD
p.o.; QD -
Result:Achieved tumor regression comparable to Selpercatinib.
Chemical Information
-
CAS No. 2760847-82-1
-
Molecular Weight 869.04
-
Formula C48H57FN12O3
-
SMILES
CCC1(CCN(CC1)C2=NC=C(C=C2)C3=NC(C4=CN(N=C4)[C@H]5CC[C@@H](CC5)N6CCC(CC6)C7=C(C=C(C=C7)NC8CCC(NC8=O)=O)F)=CN9N=CC(C#N)=C39)C(NC(C)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
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
PROTAC RET Degrader 1 Related Classifications
HY-178964 Related Classifications
Powered by Bioz