RP04340
RP04340 is an orally active, selective pan-KRAS PROTAC degrader. RP04340 hijacks the CRBN E3 ligase and the cellular proteasome system to degrade KRAS, without degrading HRAS, NRAS, or common CRBN neosubstrates. RP04340 inhibits KRAS downstream signaling pathways, including pERK and DUSP6. RP04340 exhibits anticancer activity in various KRAS-mutant cancers. RP04340 can be used to study kras-driven cancers, including pancreatic ductal adenocarcinoma, colorectal cancer, and lung adenocarcinoma.
(Pink: K-RAS ligand (HY-189223); Blue: Cereblon E3 ligase ligand; Black: linker (HY-W007836)).
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- CAS No.: 3118096-98-0
- Formule: C56H61F5N10O5
- Masse moléculaire:1049.14
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Stockage:
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]
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Activité biologique
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Chemical Information
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- Références
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Activité biologique
Description
IC50 & Target
[1]|
K-RAS |
Cereblon |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| MIA PaCa-2 | DC50 |
2 nM
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Degradation of KRAS protein in MIA PaCa-2 (KRAS G12C) cells incubated for 24 h measured by KRAS degradation immunoblot assay.
Degradation of KRAS protein in MIA PaCa-2 (KRAS G12C) cells incubated for 24 h measured by KRAS degradation immunoblot assay.
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42679154 |
| NCI-H727 | DC50 |
13.1 nM
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Degradation of KRAS protein in NCI-H727 (KRAS G12V) cells incubated for 24 h measured by KRAS degradation immunoblot assay.
Degradation of KRAS protein in NCI-H727 (KRAS G12V) cells incubated for 24 h measured by KRAS degradation immunoblot assay.
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42679154 |
| MIA PaCa-2 | IC50 |
8.8 nM
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Antiproliferative activity against MIA PaCa-2 (KRAS G12C) cells assessed as reduction in cell viability incubated for 72 h by Cell Titer-Glo assay.
Antiproliferative activity against MIA PaCa-2 (KRAS G12C) cells assessed as reduction in cell viability incubated for 72 h by Cell Titer-Glo assay.
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42679154 |
| NCI-H727 | IC50 |
3.7 nM
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Antiproliferative activity against NCI-H727 (KRAS G12V) cells assessed as reduction in cell viability incubated for 72 h by Cell Titer-Glo assay.
Antiproliferative activity against NCI-H727 (KRAS G12V) cells assessed as reduction in cell viability incubated for 72 h by Cell Titer-Glo assay.
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42679154 |
In Vitro
RP04340 (0-1000 nM; 24 h) is a potent selective KRAS degrader that achieves low nanomolar DC50 values in KRASG12D AsPC-1, KRASG12C MIA PaCa-2, and KRASG12V NCI-H727 cell lines, with no observed activity against HRAS or NRAS[1].
RP04340 (0.1-1000 nM; 72 h) demonstrates potent low nanomolar antiproliferative activity in KRASG12D AsPC-1, KRASG12C MIA PaCa-2, and KRASG12V NCI-H727 cell lines[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:AsPC-1 (KRAS G12D), MIA PaCa-2 (KRAS G12C), NCI-H727 (KRAS G12V), PK-59 (KRAS G12D)
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Concentration:0, 0.1, 1, 10, 100, 1000 nM
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Incubation Time:24 h
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Result:Potently degrades KRAS protein across multiple KRAS mutant lines, with DC50 values of 13.5 nM (AsPC-1), 2 nM (MIA PaCa-2), 13.1 nM (NCI-H727), and achieves >80% Dmax for KRAS degradation.
Does not induce degradation of HRAS or NRAS even at 1000 nM in PK-59 cells.
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Cell Line:AsPC-1 (KRAS G12D), MIA PaCa-2 (KRAS G12C), NCI-H727 (KRAS G12V)
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Concentration:0.1, 1, 10, 100, 1000 nM
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Incubation Time:72 h
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Result:Exhibits high antiproliferative activity in the tested KRAS mutant cell lines, with IC50 values of 20.9 nM (AsPC-1), 8.8 nM (MIA PaCa-2), and 3.7 nM (NCI-H727).
Parmacokinetics
| Species | Dose | Route | AUC |
|---|---|---|---|
| Mice[1] | 10 mg/kg | p.o. | 1309 ng·h/mL |
In Vivo
RP04340 (25-100 mg/kg; p.o.; once daily; 21 days) induces dose-dependent tumor regression in the MIA PaCa-2 KRASG12C xenograft model, with a tumor regression rate of up to 59.5% at a dose of 100 mg/kg[1].
RP04340 (25-100 mg/kg; p.o.; once daily; 28 days) administered orally once daily for 28 days in the NCI-H727 KRASG12V xenograft model achieves a tumor growth inhibition rate of 75.4% at a dose of 100 mg/kg[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Balb/c nude mice (6-8 week old female)[1]
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Dosage:100 mg/kg (single administration); 100 mg/kg (once daily for 15 consecutive days)
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Administration:p.o. (single administration); p.o. (once daily for 15 consecutive days)
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Result:Reached 1013 ng/g tumor RP04340 concentration (vs 278 ng/mL in plasma), 56.7% KRAS protein degradation, 67% pERK suppression, and 47% DUSP6 suppression after a single 100 mg/kg oral dose.
Reached 20133 ng/g tumor RP04340 concentration at 24 h (vs 1032 ng/mL in plasma), 76.6% KRAS protein degradation, 75% pERK inhibition, 99.8% DUSP6 suppression, and 18712 h·ng/mL steady-state AUC0-24 in plasma after 15 consecutive 100 mg/kg once-daily oral doses.
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Animal Model:Balb/c nude mice (6-8 week old female)[1]
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Dosage:25 mg/kg; 50 mg/kg; 100 mg/kg
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Administration:p.o.; once daily; 21 days
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Result:Achieved 15.1% tumor regression after 21 days of continuous dosing at the 25 mg/kg once-daily dose.
Produced 27.2% tumor regression after 21 days of continuous dosing at the 50 mg/kg once-daily dose.
Resulted in 59.5% tumor regression after 21 days of continuous dosing at the 100 mg/kg once-daily dose.
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Animal Model:Balb/c nude mice (6-8 week old female)[1]
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Dosage:25 mg/kg; 50 mg/kg; 100 mg/kg
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Administration:p.o.; once daily; 28 days
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Result:Resulted in 60.3% tumor growth inhibition after 28 days of continuous administration at the 25 mg/kg once-daily dose.
Yielded 60.9% tumor growth inhibition after 28 days of continuous administration at the 50 mg/kg once-daily dose.
Produced 75.4% tumor growth inhibition after 28 days of continuous administration at the 100 mg/kg once-daily dose.
Chemical Information
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CAS No. 3118096-98-0
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Masse moléculaire 1049.14
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Formule C56H61F5N10O5
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SMILES
O=C(N(C1=NN(C)C2=CC(C3CCN(C4CC5(CCN(C[C@]6(COC7=NC(N(CCC8)C[C@]98CCO9)=C(C=NC(C%10=C%11C(CC)=C(F)C=CC%11=CC(O)=C%10)=C%12F)C%12=N7)C(F)(F)C6)CC5)C4)CC3)=C(F)C=C12)CC%13)NC%13=O
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
RP04340 Related Classifications
HY-189222 Related Classifications
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