GENFLEET-B molecular glue Pan RAS(ON) inhibitor GFH276 has completed enrollment of the first patient in the Phase I/II clinical trial for patients with RAS mutant cancers

According to the Zhitong Finance APP, GENFLEET-B (02595) announced that the first patient has recently been enrolled in the Phase I/II trial of GFH276 for the treatment of RAS-mutant advanced solid tumors. The National Medical Products Administration approved the clinical trial application for GFH276 to enter an open-label, multi-center study at the beginning of September. This product is a molecular glue Pan RAS(ON) inhibitor independently developed by GENFLEET, with global rights. Frost & Sullivan data indicates that the number of cancer cases worldwide is expected to reach nearly 22 million by 2025, with approximately 30% (over 6.5 million) of cancer patients having different subtypes of RAS (KRAS, NRAS, HRAS) gene mutations in their tumor cells. Currently, there are no pan-RAS targeted drugs approved for market globally, and GFH276 is among the top three in the global development of Pan RAS(ON) inhibitors. GFH276 is the third RAS-targeted therapy in GENFLEET's pipeline to enter clinical research, following the successful market launch of the KRAS G12C inhibitor, GFH925, and GFH375, which is in the leading tier of oral KRAS G12D inhibitor development. The Phase Ia clinical trial of GFH276 will be conducted at approximately 10 research centers, including the Sun Yat-sen University Cancer Prevention and Treatment Center and the Shanghai Fudan University Affiliated Cancer Hospital. The main objectives of the overall Phase I trial are to assess the safety/tolerability of GFH276 in patients and to determine the recommended dose for Phase II, as well as to evaluate the pharmacokinetic characteristics and preliminary efficacy of GFH276. GFH276 can target and inhibit most activated wild/mutant RAS proteins. According to poster data from the 2025 AACR Annual Meeting: GFH276 demonstrated lower effective doses and better pharmacokinetic characteristics compared to similar overseas products in various RAS mutant tumor models, and showed good safety and targeted specificity in kinase selectivity and safety-related target tests; additionally, it maintained strong activity and demonstrated multi-drug resistance potential in various mechanism-induced KRAS inhibitor-resistant cell lines. Dr. Yu Wang, Chief Medical Officer of GENFLEET, stated: "Through the successful development of GFH925 and GFH375, we have accumulated rich experience in the research and development of RAS-targeted therapies. GFH276 is the first molecular glue product in our pipeline to enter clinical research, and our self-developed EGFR-Pan RAS ADC has also entered the clinical application stage. The innovative products with multiple targets and diversified molecular forms demonstrate the depth of our RAS therapy matrix. We also look forward to GFH276 showing good efficacy in clinical research and benefiting patients worldwide." RAS proteins act as binary molecular switches, toggling between an inactive state bound to GDP (guanosine diphosphate) and an active state bound to GTP (guanosine triphosphate), thereby regulating pathways such as RAF-MEK-ERK and PI3K-AKT-mTOR. Oncogenic mutations in RAS lead to the loss of its GTPase activity, resulting in RAS proteins predominantly existing in an activated GTP-bound form, which can lead to malignant cell proliferation and changes in biological behavior. The RAS family of proteins is mainly divided into three categories: KRAS, HRAS, and NRAS, among which KRAS mutations are one of the most common gene mutations in tumors GFH276 is a uniquely designed oral molecular glue Pan RAS(ON) inhibitor that employs a tri-complex mechanism of action (CypA-GFH276-RAS), allowing for more efficient inhibition of most activated states of wild-type/mutant RAS protein subtypes, including common KRAS mutations (G12C, G12D, G12V, etc.). Preclinical studies have shown that GFH276 exhibits dose-dependent anti-tumor activity and promotes tumor regression in various KRAS mutant tumor models; compared to first-generation SIIP (switch II pocket) binding KRAS inhibitors, GFH276 is expected to overcome the limitations of adaptive and acquired resistance caused by existing drugs