Setidegrasib (ASP-3082) is a PROTAC KRAS degrader ( DC50: 37 nM). Setidegrasib induces the degradation of G12D-mutation KRAS protein. Setidegrasib suppresses p-ERK, p-AKT, p-S6 levels in AsPC-1 cells. Setidegrasib exhibits anti-tumor activity in various cancer xenograft models in mice. Setidegrasib can be used in studies involving KRAS(G12D)-mutated solid tumors, such as non-small cell lung cancer [1] [2] [3] [4]. (Pink: K-RAS ligand; Blue: VHL ligand; Black: linker ).
In Vivo, Setidegrasib (0.3-30 mg/kg, i.v., once/twice weekly, 14-22 days) exhibits dose-dependent anti-tumor activity in PK-59, LXFA 1125 NSCLC PDX, AsPC-1 (pancreatic) and GP2d (colorectal) KRAS(G12D)-mutated xenograft models of Balb/c nu/nu nude mice[1][2].
In Vitro, Setidegrasib (Example 8) (24 h) inhibits ERK phosphorylation in G12D-mutant KRAS-positive pancreatic cancer strain AsPC-1, with an IC50 of 15 nM[1]. Setidegrasib (6 days) inhibits anchorage-independent cell growth against G12D-mutant KRAS-positive pancreatic cancer strain AsPC-1, with an IC50 of 23 nM[1]. Setidegrasib (6 days) potently inhibits proliferation of multiple KRAS(G12D)-mutated cancer cell lines (PK-59, HPAC, GP2d, GP5d) in 3D assay, while showing weak activity (IC50 > 10 μM) against KRAS(WT) cells (A375, HT-29) and other KRAS mutants (G12V, G12C, G13D) via CellTiter-Glo assay[2]. Setidegrasib (1 μM, 4-24 h) selectively reduces KRAS(G12D) and DUSP4 (a MAPK-dependent gene) levels in AsPC-1 cells[2]. Setidegrasib (30-300 nM, 6-72 h) sustains KRAS(G12D) degradation (including GTP-bound form) and suppresses p-ERK, p-AKT, p-S6 levels in AsPC-1 cells[2].
References:
[1]. Yoshinari, et al. Preparation of quinazoline-linked (4R)-4-hydroxy-L-prolinamide compounds for inducing degradation of G12D-mutation KRAS protein: World Intellectual Property Organization, WO2022173032[P]. 2022-08-18.
[2]. Yoshinari T, et al. Discovery of KRAS(G12D) selective degrader ASP3082. Commun Chem. 2025 Aug 23;8(1):254.
[3]. Paz-Ares L, et al. 1O Efficacy and safety of setidegrasib in patients (pts) with advanced NSCLC with KRAS G12D mutation[J]. ESMO Open, 2026, 11.
[4]. Eguchi K, et al. KRAS-Targeted Therapy in Non–Small Cell Lung Cancer: Current Standards, Resistance[J]. J Clin. Jan-Feb, 2026, 76(1): e70043.
In Vivo, Setidegrasib (0.3-30 mg/kg, i.v., once/twice weekly, 14-22 days) exhibits dose-dependent anti-tumor activity in PK-59, LXFA 1125 NSCLC PDX, AsPC-1 (pancreatic) and GP2d (colorectal) KRAS(G12D)-mutated xenograft models of Balb/c nu/nu nude mice[1][2].
In Vitro, Setidegrasib (Example 8) (24 h) inhibits ERK phosphorylation in G12D-mutant KRAS-positive pancreatic cancer strain AsPC-1, with an IC50 of 15 nM[1]. Setidegrasib (6 days) inhibits anchorage-independent cell growth against G12D-mutant KRAS-positive pancreatic cancer strain AsPC-1, with an IC50 of 23 nM[1]. Setidegrasib (6 days) potently inhibits proliferation of multiple KRAS(G12D)-mutated cancer cell lines (PK-59, HPAC, GP2d, GP5d) in 3D assay, while showing weak activity (IC50 > 10 μM) against KRAS(WT) cells (A375, HT-29) and other KRAS mutants (G12V, G12C, G13D) via CellTiter-Glo assay[2]. Setidegrasib (1 μM, 4-24 h) selectively reduces KRAS(G12D) and DUSP4 (a MAPK-dependent gene) levels in AsPC-1 cells[2]. Setidegrasib (30-300 nM, 6-72 h) sustains KRAS(G12D) degradation (including GTP-bound form) and suppresses p-ERK, p-AKT, p-S6 levels in AsPC-1 cells[2].
References:
[1]. Yoshinari, et al. Preparation of quinazoline-linked (4R)-4-hydroxy-L-prolinamide compounds for inducing degradation of G12D-mutation KRAS protein: World Intellectual Property Organization, WO2022173032[P]. 2022-08-18.
[2]. Yoshinari T, et al. Discovery of KRAS(G12D) selective degrader ASP3082. Commun Chem. 2025 Aug 23;8(1):254.
[3]. Paz-Ares L, et al. 1O Efficacy and safety of setidegrasib in patients (pts) with advanced NSCLC with KRAS G12D mutation[J]. ESMO Open, 2026, 11.
[4]. Eguchi K, et al. KRAS-Targeted Therapy in Non–Small Cell Lung Cancer: Current Standards, Resistance[J]. J Clin. Jan-Feb, 2026, 76(1): e70043.