Zamaporvint

• CAT Number: I041064
• CAS Number: 1900754-56-4
• Molecular Formula: C21H16F3N7O
• Molecular Weight: 439.39
• Purity: ≥95%
• Synonyms: 2-[5-methyl-4-[2-(trifluoromethyl)pyridin-4-yl]imidazol-1-yl]-N-(5-pyrazin-2-ylpyridin-2-yl)acetamide
• InChI: InChI=1S/C21H16F3N7O/c1-13-20(14-4-5-27-17(8-14)21(22,23)24)29-12-31(13)11-19(32)30-18-3-2-15(9-28-18)16-10-25-6-7-26-16/h2-10,12H,11H2,1H3,(H,28,30,32)
• InChIKey: QMLOYDPILBUVBV-UHFFFAOYSA-N
• SMILES: CC1=C(N=CN1CC(=O)NC2=NC=C(C=C2)C3=NC=CN=C3)C4=CC(=NC=C4)C(F)(F)F

Zamaporvint (RXC004) is an orally active and selective inhibitor of Wnt. Zamaporvint targete membrane-bound o-acyltransferase Porcupine and inhibited Wnt ligand palmitoylation, secretion, and pathway activation. Zamaporvint displays a favorable pharmacokinetic profile and shows potent antiproliferative effects in Wnt ligand-dependent colorectal and pancreatic cell lines. Zamaporvint possesses multiple antitumor mechanisms and can be used in cancer research[1].
Zamaporvint (300 nM, 48 h) treatment of L- wnt3a cells reduce the ability of conditioned medium to activate the β-catenin-responsive luciferase reporter gene in a concentration-dependent manner, with an IC50 of 64 pM, and the addition of recombinant Wnt3a restore the luciferase activity, suggesting no effect on downstream Wnt signaling[1].
The effect of Zamaporvint (100 nM, 24 hr) on proliferation reflects a concentration-dependent downregulation of c-Myc mRNA. Reduced the proportion of cells in S phase and strongly suppressed the expression of the mitotic marker phospho-histone-H3 in cells with abnormal upstream components of the Wnt pathway, indicative of cell cycle arrest, and was found to have reduced immunosuppression at the same dose as after administration Sexual support[1] .
Zamaporvint (20 μM, 18 h) in plasma across species ranged from 2.5% to 7.5%, microsomal CLint values ranged from 3.9 to 31.6 μL/min?mg, with mouse having the lowest and dog the highest predicted clearances, rodents and humans display low clearance[1].
Zamaporvint (10 μM, 2 h) has good intrinsic permeability, showing some evidence of efflux in MDR1-MDCKII cells but not in Caco-2 cells[1].
Zamaporvint (1.5 mg/kg or 5 mg/kg orally twice daily, or 5 mg/kg Zamaporvint orally once daily, for 28 days) reduces in tumor growth, and inhibition of Wnt-responsive gene expression including cMyc, was observed in the Wnt ligand–dependent SNU-1411, AsPC1, and HPAFII models, and no effected tumor growth in the Wnt ligand–independent HCT116 xenograft mode[1].
Zamaporvint (1.5 mg/kg, 5 mg/kg, once daily) reduces Ki67-positive cells in the total tumor area, and its effect is more pronounced in differentiated tumor areas, and by inhibiting immune evasion in the B16F10 “cold” tumor model Antitumor effect [1].
Zamaporvint (1.5 or 5 mg/kg once daily) stimulates host tumor immunity, reduces resident myeloid-derived suppressor cells within B16F10 tumors and synergizing with anti-programmed cell death protein-1 (PD-1, HY-P73361) to increase CD8+/regulatory T cell ratios within CT26 tumors[1].
Pharmacokinetic Parameters of Zamaporvint in Mice. [1]

species
Dose (i.v./p.o., mg/kg)
Cmax (p.o., μM)
C24 h (p.o., μM)
AUCinf (p.o., μM.h)
Cl (mL/min/kg)
Vss (L/kg)
F (p.o., %)
T1/2 (hr)

mouse
2/5
7.6
0.002
33.9
2.9
0.40
48
1.8

rat
2/5
3.6
0.009
10.5
5.8
0.64
31
2.5

dog
2/5
10.4
0.012
8.6
8.9
0.39
137
0.8

Reference

[1]. Phillips C, The Wnt Pathway Inhibitor RXC004 Blocks Tumor Growth and Reverses Immune Evasion in Wnt Ligand-dependent Cancer Models. Cancer Res Commun. 2022 Sep 2;2(9):914-928.
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