KRAS represents the most frequently mutated oncogene in human cancers, with mutations occurring in approximately 30% of all malignancies. Significant progress has been made in RAS-targeted therapies over recent years. These include the FDA approval of G12C inhibitors such as sotorasib and adagrasib that target the OFF state of RAS, as well as the ongoing development of various non-G12C inhibitors and ON-state RAS inhibitor. Here we present AUBE00, a novel cyclic peptide that selectively binds to the OFF state of KRAS. AUBE00 demonstrates equivalent binding affinity across a broad spectrum of KRAS mutations. In vitro studies revealed potent antiproliferative activity against cancer cell lines harboring various KRAS alterations.Pharmacokinetic evaluation across multiple species demonstrated favorable oral bioavailability of AUBE00. Oral administration resulted in robust in vivo antitumor efficacy in preclinical models. The intracellular equilibrium between ON and OFF states of the KRAS protein is thought to vary depending on mutation types. Wild-type RAS predominantly exists in the OFF state under physiological conditions. The G13D mutant retains higher susceptibility to NF1-dependent hydrolysis compared to G12X mutants, suggesting a relatively higher proportion of OFF-state conformation. Based on this biological insight, we compared efficacy of AUBE00 with RMC-6236, a pan-RAS(ON) inhibitor among models with various KRAS alterations. Our findings demonstrate that AUBE00 exhibits superior antitumor activity against cancers with KRAS wild-type amplification or KRAS G13D mutations compared to RMC-6236. Notably, RAS wild-type colorectal cancers typically show high dependency on EGFR signaling, with anti-EGFR antibodies established as standard therapy. This clinical observation suggests that downstream activation of wild-type RAS signaling significantly contributes to cancer proliferation and progression. Our investigations revealed that AUBE00 demonstrates significant antitumor activity in RAS wild-type colorectal cancer models. Furthermore, combination treatment with cetuximab and AUBE00 exhibited synergistic antiproliferative effects in vitro. In conclusion, our preclinical data establish AUBE00 as a promising therapeutic option for cancers harboring KRAS mutations as well as RAS wild-type colorectal cancer. AUBE00 is currently being evaluated in a Phase 1 dose escalation study to assess its safety, tolerability, and preliminary efficacy in patients with advanced solid tumors.