CH091138 is a potent and selective KRASG12D PROTAC degrader, exhibiting a DC50 value of 148.3 nM in HeLa cells and 469.8 nM in AsPC-1 cells. It selectively targets both exogenous and endogenous KRASG12D through the VHL-mediated ubiquitin-proteasome system, without affecting KRASWT or other KRAS mutants (G12C/G12S/G12V). CH091138 demonstrates significant antitumor activity by inducing apoptosis (apoptosis) in tumor cells and is applicable for research in pancreatic and colon cancers.

NEP108:3.8 μM (DC50)

CH091138 effectively blocks downstream KRAS signaling pathways in AsPC1 cells with the KRAS G12D mutation at concentrations of 0-30 μM over 24 hours. It exhibits a GI50 of 0.75 μM in KRAS G12D mutant AsPC1 cells when used at 0.01-100 μM over 3 days. The compound inhibits migration and invasion of AsPC-1 cells at 1-30 μM for 24 hours. Additionally, CH091138 suppresses colony formation and induces apoptosis in AsPC-1 cells at 1-10 μM over a period of 24 hours to 21 days. The compound shows stronger growth inhibition on patient-derived organoids (PDOs) with the KRAS G12D mutation compared to wild-type KRAS PDOs at 0-100 μM over 5 days.

In the AsPC-1 tumor xenograft model, CH091138 (administered at 60 mg/kg intraperitoneally every three days for 29 days) demonstrates significant in vivo antitumor activity with minimal body weight changes.