Abstract 4384: SYNB021225: a potent oral pan-KRAS peptide inhibitor that can address unmet needs of small molecule inhibitors
Authors: Michael Poss, Caihong Zhou, Cheng Lu, Ruochi Zhang, Yu Wang, Yuanpeng Xiong, Xin Gao, Xiao Zhang, Yan Degenhardt
Journal: Cancer Research (2025)

Abstract KRAS mutations are present in 30% of cancer patients, underscoring the importance of KRAS as a critical target for drug development. Despite the advancements in small molecule inhibitors targeting specific KRAS mutations, such as G12C and G12D, significant challenges persist in addressing other prevalent mutations such as G12V. Furthermore, small molecule inhibitors predominantly target the GDP-bound form of KRAS due to accessibility of the SWITCH II pocket, even though most mutant KRAS proteins in cancer cells are in the activated GTP-bound form. Peptide drugs have emerged as promising alternatives due to their exceptional binding affinity and specificity, along with their reduced dependency on the presence of a well-defined binding pocket. Utilizing Syneron’s innovative technology, we have successfully developed cyclic peptides capable of cell penetration and oral bioavailability, to overcome some of the limitations associated with small molecule KRAS therapeutics. SYNB021225 is a potent pan-KRAS inhibitor effective against multiple KRAS mutations, including G12V. With sub-nanomolar potency in both binding and in vitro cell killing, SYNB021225 induces tumor regression at oral doses of 10-20 mpk administered once daily. Besides expanding the treatable patient population, its broad targeting profile can also potentially address tumor heterogeneity and mitigate resistance. SYNB021225 inhibits both KRAS-ON and KRAS-OFF forms, directly disrupting the interaction between GTP-bound KRAS and RAF. Given that most mutant KRAS proteins in cancer cells are in the activated GTP-bound form, comparing to small molecules that mainly target the GDP-bound KRAS, this dual action offers potential advantage in enhancing efficacy as well as overcoming resistance from activated Receptor Tyrosine Kinases like EGFR. Indeed, in the in vitro proliferation assay, the potency of SYNB021225 remained unaffected when treated with EGF. Furthermore, SYNB021225 demonstrates efficacy against KRAS wild-type amplified tumors, which are resistant to KRAS-ON only molecular glue inhibitors. Current small molecule inhibitors often fail to maintain sustained p-ERK inhibition, impacting overall survival. In preclinical studies, SYNB021225 has shown prolonged tumor retention and p-ERK suppression lasting up to 72 hours, that may translate to improved clinical efficacy. Unlike small molecules, peptides such as SYNB021225 are metabolized by proteases and excreted via the kidneys, minimizing liver toxicity. This profile makes SYNB021225 more suitable for combination therapies, such as with anti-PD1 agents, without exacerbating the liver inflammation as seen in the clinic with small molecule inhibitors. Currently, SYNB021225 is being prepared for clinical development. Citation Format: Michael Poss, Caihong Zhou, Cheng Lu, Ruochi Zhang, Yu Wang, Yuanpeng Xiong, Xin Gao, Xiao Zhang, Yan Degenhardt. SYNB021225: a potent oral pan-KRAS peptide inhibitor that can address unmet needs of small molecule inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4384.