2. GPCR/G Protein MAPK/ERK Pathway Stem Cell/Wnt
  3. Ras ERK
  4. RNK08954

RNK08954 is an orally active KRASG12D inhibitor with a Kd of 0.0395 nM. RNK08954 selectively binds the inactive GDP-bound KRASG12D form, suppresses downstream KRAS-mediated signaling pathways p-ERK1/2 experssion. RNK08954 inhibits KRASG12D-mutant cell proliferation, induces G0-G1 cell cycle arrest, and inhibits tumor growth in mouse xenograft models. RNK08954 can be used for the research of non-small cell lung cancer, pancreatic ductal adenocarcinoma.

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RNK08954

RNK08954 Estructura química

No. CAS : 3032602-44-8

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RNK08954 Related Antibodies

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Descripciòn

RNK08954 is an orally active KRASG12D inhibitor with a Kd of 0.0395 nM. RNK08954 selectively binds the inactive GDP-bound KRASG12D form, suppresses downstream KRAS-mediated signaling pathways p-ERK1/2 experssion. RNK08954 inhibits KRASG12D-mutant cell proliferation, induces G0-G1 cell cycle arrest, and inhibits tumor growth in mouse xenograft models. RNK08954 can be used for the research of non-small cell lung cancer, pancreatic ductal adenocarcinoma[1].

IC50 & Target[1]

KRas G12D

0.0395 nM (Kd)

ERK1

 

ERK2

 

In Vitro

RNK08954 potently and selectively binds to inactive GDP-bound KRASG12D with a Kd of 39.5 pM, with significantly lower affinity for other KRAS variants and wild-type KRAS[1].
RNK08954 (5-1250 nM; 6-72 h) potently inhibits KRAS downstream signaling in KRASG12D-mutant SW1990 cells, with an IC50 of <5.14 nM for p-ERK1/2 inhibition at 6 hours, and sustained inhibition through 72 hours[1].
RNK08954 (72 h) potently inhibits viability of KRASG12D-mutant human tumor cell lines with a median IC50 of 10.8 nM, and shows high selectivity against KRAS wild-type and non-G12D KRAS-mutant cells[1].
RNK08954 induces G0-G1 cell cycle arrest and cell death in KRASG12D-mutant SW1990 cells[1].

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

RNK08954 Related Antibodies

Western Blot Analysis[1]

Cell Line: Human pancreatic adenocarcinoma SW1990 cells (KRASG12D-mutant)
Concentration: 5, 15, 46, 140, 417, 1250 nmol/L
Incubation Time: 6-72 h
Result: Caused concentration-dependent inhibition of p-ERK1/2 levels as early as 6 hours after treatment, with this effect sustained through 72 hours.
Achieved IC50 values for p-ERK1/2 inhibition of <5.14 nM at 6 hours, 5.18 nM at 24 hours, 10.67 nmol/L at 48 hours, and 9.53 nM at 72 hours.
Showed time- and concentration-dependent inhibition of p-AKT levels.
Parmacokinetics
Species Dose Route AUC0-24 CL Vss T1/2 Tmax F Cmax
Mice[1] 5 mg/kg i.v. 757 ng·h/mL 6.23 L/h/kg 36.5 L/kg 7.86 h / / /
Mice[1] 60 mg/kg i.g. 36.5 ng·h/mL / / / 2 h 7.56 % 214 ng/mL
In Vivo

RNK08954 (3-200 mg/kg; p.o.; once or twice daily; 30-35 days) induces dose-dependent tumor growth inhibition and regression in GP2d colorectal cancer xenografts mice, with 70% tumor regression at 60 mg/kg once daily and near-complete regression at higher twice-daily doses[1].
RNK08954 (10-200 mg/kg; p.o.; once daily for 5 days) dose-dependently inhibits KRAS downstream signaling (p-ERK, p-S6, DUSP6) in GP2d xenografts mice, with significantly higher drug exposure in tumor tissue compared to plasma[1].
RNK08954 (25-100 mg/kg; p.o.; once daily, twice daily; 28 days) potently inhibits tumor growth in SW1990 pancreatic cancer xenografts mice, with near-complete tumor regression observed at 100 mg/kg twice daily[1].
RNK08954 (25-100 mg/kg; p.o.; once daily, twice daily; 42 days) achieves complete tumor regression in Panc 04.03 pancreatic cancer xenografts mice at a dose of 100 mg/kg twice daily[1].
RNK08954 (50-200 mg/kg; p.o.; twice daily; 35 days) drives dose-dependent tumor growth inhibition in A427 non-small cell lung cancer xenografts mice[1].
RNK08954 (100-200 mg/kg; p.o.; once daily, twice daily; 35 dyas) potently inhibits tumor growth in multiple KRASG12D-mutant pancreatic cancer PDX mice models[1].
RNK08954 (200 mg/kg; p.o.; once daily; 28 dyas) induces significant tumor shrinkage in an orthotopic HPAF-II-luc pancreatic cancer mice models at 200 mg/kg once daily[1].
RNK08954 (100 mg/kg; p.o.; once daily) inhibits tumor growth and modulates the tumor immune microenvironment by expanding CD8+ T cells in CT-26 syngeneic mice models, with enhanced efficacy when combined with anti-PD-1[1].

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

Animal Model: BALB/c nude with GP2d colorectal cancer xenografts (female, 6-8 weeks old)[1]
Dosage: 6 mg/kg; 20 mg/kg; 60 mg/kg (once daily); 3 mg/kg; 10 mg/kg; 30 mg/kg; 100 mg/kg; 200 mg/kg (twice daily)
Administration: p.o.; 30 or 35 days
Result: Induced 70% tumor regression at 60 mg/kg once daily.
Drove substantial tumor regression at 100 mg/kg twice daily and 200 mg/kg twice daily, with tumor volumes reaching near or below 16 mm3 by day 30.
Showed dose-dependent tumor growth inhibition.
Was well tolerated with no significant body weight changes.
Animal Model: BALB/c nude with GP2d colorectal cancer xenografts (female, 6-8 weeks old)[1]
Dosage: 10 mg/kg; 30 mg/kg; 100 mg/kg; 200 mg/kg
Administration: p.o.; once daily for 5 days
Result: Showed significant, sustained inhibition of p-ERK in tumor tissue, with inhibition detectable as early as 4 hours and persisting through 24 hours across all 10, 30, 100 mg/kg doses.
Inhibited p-S6 in tumor tissue at 100 mg/kg.
Resulted in ~80% inhibition of DUSP6 mRNA expression at 24 hours post single 200 mg/kg dose.
Achieved tumor exposure 51-fold, 119-fold, and 223-fold higher than plasma exposure at 10, 30, and 100 mg/kg, respectively.
Ensayo clínico
Peso molecular

638.71

Fòrmula

C36H36F2N6O3
No. CAS
SMILES

C#CC1=C(C=CC2=CC(O)=CC(C3=NC(OC)=C4C(N5CC6CCC(N6)C5)=NC(OCC7(CC7)CN8CC9CC9C8)=NC4=C3F)=C21)F
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Room temperature in continental US; may vary elsewhere.
Almacenamiento

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RNK08954 Related Classifications

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  • Do most proteins show cross-species activity?

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Keywords:

RNK089543032602-44-8RNK 08954RNK-08954RasERKExtracellular signal regulated kinasesSW1990 cellsCD8 T cellsA427pancreatic ductal adenocarcinomaKRASKRASG12Panc 04.03 pancreatic cancer xenograftsmouse xenograft modelsGP2dcolorectal cancer xenograftsnon-small cell lung cancerInhibitorinhibitorinhibit

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