LUNA18 is an orally-available cyclic peptide KRAS and ERK inhibitor. LUNA18 phosphorylates ERK and AKT and decreases cell proliferation in RAS-mutated cancer cells. LUNA18 exhibits RAS signal inhibition and potent anti-cancer activities through inhibiting interaction between RAS and guanine nucleotide exchange factors (GEFs) in a mouse xenograft model. LUNA18 shows significant cellular efficacy against cell lines with KRAS genetic alterations, such as colon cancer, stomach cancer, non-small cell lung cancer and pancreaticcancer.
LUNA18 (2 μmol/L, 36 h) robustly inhibits proliferation of NCI-H2122, MiaPaCa-2, NCI-H441, LS 180, GSU cell lines, which is a selective RAS inhibitor[3].LUNA18 (0-100 nM, 4 h) decreases GTP-KRAS, pERK1/2 and pAKT expression in a concentration-dependent manner in NCI-H441 cell lines[3].
LUNA18 (10 mg/kg, p.o., once daily for 14 days) results in dose-dependent antitumor activity without any marked body weight loss in NCI-H441 xenograft mouse model[3].PK parameters of LUNA18[3]
References:
[1]. Tanada M, et al. Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor. J Am Chem Soc. 2023 Aug 2;145(30):16610-16620.
[2]. Sase H, et al. Anti-tumor activity of orally-available cyclic peptide LUNA18 through direct RAS inhibition in RAS-altered tumors[J]. Cancer Research, 2024, 84(6_Supplement): 1654-1654. [3]. Ohta A, et al. Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets[J]. J Am Chem Soc. 2023 Nov 8;145(44):24035-24051.