ZJK-807 is a selective, cereblon (CRBN)-based proteolysis-targeting chimera (PROTAC) degrader of KRASG12D with DC50 of 79.5 nM in AsPC-1 cells (Dmax=92%), with minimal impact on wild-type KRAS or other mutants (G12C/S/V, G13D) KRAS proteins.
ZJK-807 combines an MRTX1133 analog with a VHL ligand, achieves efficient KRASG12D degradation.
ZJK-807 effectively reduces KRASG12D levels by 85 ± 2% at 1 μM and achieved an IC50 value of 0.22 uM in AsPC-1 cell line.
ZJK-807 is more effective in degrading KRASG12D in pancreatic cancer cells AsPC-1 compared to colorectal GP2D and gastric cancer cells AGS.
ZJK-807 exhibits antiproliferative effects on KRASG12D mutant cell lines, with IC50 values of 219.6 ± 43.8 nM in AsPC-1, 273.5 ± 58.9 nM in AGS, and 1110 ± 107.2 nM in GP2D cells, with no substantial antiproliferative activity in cell lines with wild-type or other KRAS mutations.
ZJK-807 has the potential to overcome acquired resistance to MRTX1133.
ZJK-807 (30 mg/kg, QD, SC) demonstrated in vivo antitumor efficiency in the AsPC-1 xenograft mice.