| Field | Specification |
|---|---|
| Target | |
| CAS no. | |
| Applications | |
| Molecular weight | |
| Molecular formula | C30H38N6O |
| Purity | |
| SMILES | |
| Form | Solid |
| Storage | |
| Shipping | |
| Catalog no. (Mfr.) | |
| Main SKU |
Compound Overview
TH-Z827 is a selective KRAS G12D inhibitor, active against both GDP-bound and GMPPNP-bound KRAS G12D but inactive against wild-type KRAS and KRAS G12C. It blocks the KRAS G12D–CRAF interaction with an IC50 value of 42 μM and can be used for pancreatic cancer research[1][2]. It is supplied as a white to off-white solid (C30H38N6O, MW 498.66) at 95.12% purity.
Physical & Chemical Properties
| CAS Number | 2847881-81-4 |
|---|---|
| Molecular Formula | C30H38N6O |
| Molecular Weight | 498.66 g/mol |
| Purity | 95.12% |
| Appearance | Solid |
| Color | White to off-white |
| SMILES | CN(CCC1)[C@@H]1COC2=NC(N3[C@@H]4CNC[C@H]3CC4)=C5C(CN(C6=CC=CC7=C6C(C)=CC=C7)CC5)=N2 |
| Target | KRas G12D |
| Signaling Pathway | GPCR/G Protein; MAPK/ERK Pathway |
| Solubility | In Vitro: DMSO: 100 mg/mL (200.54 mM; Requires sonication; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO) |
| Storage | Powder: -20°C, 3 years; 4°C, 2 years. In solvent: -80°C, 6 months; -20°C, 1 month. |
| Shipping | Room temperature in continental US; may vary elsewhere. |
Biological Activity
IC50 & Target[1]
|
KRas G12D 42 μM (IC50) |
Literature Cited
Sources cited in this description and in the In Vitro & In Vivo Data tab. Peer-reviewed publications that used this product are listed under References.
Safety
For Research Use Only. Not for use in diagnostic or therapeutic procedures, and not for human or veterinary use. Handle in accordance with the Safety Data Sheet and your institution's chemical hygiene plan.
In Vitro
| Solvent | Solubility | Notes |
|---|---|---|
| DMSO | 100 mg/mL (200.54 mM) | requires sonication; use freshly opened DMSO (absorbed moisture lowers solubility) |
Aliquot the stock solution and store it at -80°C (up to 6 months) or -20°C (up to 1 month); avoid repeated freeze-thaw cycles.
Data provided by the manufacturer.
In Vitro
SOS-catalyzed nucleotide exchange of GDP-bound KRASG12D is potently inhibited by TH-Z827 (10 min), with an IC50 of 3.1 μM; nearly 10-fold selectivity is shown for KRASG12D over KRASG12C[1]. GDP-bound and GMPPNP-bound KRASG12D are both bound by TH-Z827 (800 μM) with similar affinities (Kd of 6.52 μM and 7.01 μM, respectively), whereas no binding to KRASWT or KRASG12C occurs[1]. The KRASG12D-CRAF interaction is blocked by TH-Z827 with an IC50 of 42 μM, and interactions involving KRAS(WT) or KRASG12C are left unaffected[1]. SOS-catalyzed GDP/GDP exchange of purified GDP-bound KRASG12D protein is potently inhibited by TH-Z827, with an IC50 of 3.1 μM[2]. Over KRAS WT and KRASG12C proteins, purified KRASG12D protein is bound and inhibited selectively by TH-Z827, and the latter two variants show no measurable binding[2]. Proliferation of KRASG12D-mutant PANC-1 and Panc 04.03 pancreatic cancer cells is inhibited by TH-Z827 (24 h), with IC50 values of 4.4 μM and 4.7 μM, respectively[1]. In KRASG12D-mutant PANC-1 and Panc 04.03 pancreatic cancer cells, MAPK and PI3K/mTOR signaling is inhibited by TH-Z827 (1-20 μM; 3 h), with reduced pERK and pAKT levels after 3 h of treatment[1].
Western Blot Analysis[1]
| Cell Line | KRAS(G12D)-mutant pancreatic cancer cell lines PANC-1 and Panc 04.03 |
|---|---|
| Concentration | 1-20 μM |
| Incubation Time | 3 h |
| Result | Reduced levels of phosphorylated ERK (pERK) in both PANC-1 and Panc 04.03 cells. Reduced levels of phosphorylated AKT (pAKT) at Thr308 and Ser473 in both PANC-1 and Panc 04.03 cells. Confirmed inhibition of MAPK and PI3K/mTOR signaling pathways. |
In Vivo
In BALB/c nude mice, TH-Z827 (i.p.; 10-30 mg/kg; on Days 38, 41, 44, 47, 50, 53, 56, 59, 62) decreases pancreatic tumor volumes in a dose-dependent manner, and the 30 mg/kg intraperitoneal dose gives a greater tumor volume reduction than the 10 mg/kg dose[1]. In C57BL/6 mice, TH-Z827 (10 mg/kg; i.p.) decreases pancreatic tumor volumes and shows synergistic antitumor activity combined with anti-PD-1 antibody[1]. In C57BL/6 mice bearing KPCpancreatic cancer xenografts, TH-Z827 acts synergistically with an anti-PD-1 antibody to decrease tumor volume[2].
| Animal Model | BALB/c nude mice[1] |
|---|---|
| Dosage | 10 mg/kg; 30 mg/kg |
| Administration | i.p.; Days 38, 41, 44, 47, 50, 53, 56, 59, 62 |
| Result | Reduced final mean tumor volume to ~120 mm3 at 10 mg/kg dose compared to vehicle control. Reduced final mean tumor volume to ~30 mm3 at 30 mg/kg dose compared to vehicle control. Caused weight loss in mice at 30 mg/kg dose. |
Data provided by the manufacturer. Numbered citations refer to the Literature Cited list in the product description.
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