Abstract The small membrane-bound GTPase KRAS functions as an on/off switch for multiple important cellular signaling pathways, including RAF/MEK/ERK and PI3K/AKT. As one of the most prevalent cancer drivers, KRAS alterations occur in approximately 17% of all solid tumors, including pancreatic, colorectal, lung adenocarcinoma, and esophagogastric cancers. Despite recent advances, KRAS G12C-selective inhibitors face clinical challenges in achieving durable therapeutic efficacy due to acquired drug resistance, while the mutational diversity of KRAS-driven cancers restricts their utility across patient populations, representing a significant unmet medical need. On the other hand, targeting all RAS proteins, including HRAS and NRAS, might raise potential toxicity risk, as the RAS family is essential in normal cells. Here, we report an oral pan-KRAS (ON/OFF) inhibitor ISM7713 that selectively targets all major oncogenic KRAS variants in both inactive and active conformations across multiple solid tumors while sparing HRAS and NRAS. Surface plasmon resonance revealed that ISM7713 binds to GDP-bound KRAS (inactive, or “off”) with picomolar affinity and to GTP-bound KRAS (active, or “on”) with sub-nanomolar affinity. Nucleotide exchange assays and RAS-cRAF binding assays further supported dual inhibitory function, together identifying sub-nanomolar IC50 values against KRAS variants (G12D, G12V, G12C, and WT). In cellular assays, ISM7713 suppressed cell growth with single-digit nanomolar IC50 values across cancer cell lines harboring major KRAS mutations or KRAS amplification, including GP2D (KRAS G12D), SW620 (KRAS G12V), NCI-H358 (KRAS G12C), and MKN1 (KRAS WT amplification). Treatment in vivo at 10-30 mg/kg (BID) induced tumor regression in multiple CDX models driven by different KRAS alterations (KRAS G12D/V/C mutations or KRAS amplification), along with dose-dependent pharmacodynamic responses, including changes in ERK phosphorylation and DUSP6 transcription. ISM7713 demonstrated reasonable solubility and permeability. In vivo, it exhibited good plasma clearance and bioavailability across mouse, rat, dog, and monkey. Additionally, mini-Ames and off-target safety panel profiling indicated no potential risk. Collectively, these findings highlight the potential of this novel molecule as a potent pan-KRAS (ON/OFF) inhibitor for the treatment of solid tumors with KRAS alterations. Citation Format: Sujing Shi, Defeng Shen, Jianping Wu, Tingting Liu, Jinxin Liu, Qingshuo Meng, Zuoxiao Shi, Suguna Rachakonda, David Gennert, Luoheng Qin, Xin Cai, Man Zhang, Feng Ren, Alex Zhavoronkov. ISM7713, a novel oral pan-KRAS (ON/OFF) inhibitor, shows robust anti-tumor activity in solid tumors with KRAS alterations abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 425.
Shi et al. (Fri,) studied this question.