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GenFleet Therapeutics announced the preclinical data of GFH603, a molecular glue-like candidate, were featured in a poster presentation at the 2026 American Association for Cancer Research (AACR) Annual Meeting on April 19 local time. As an allosteric activator of the KEAP1-CUL3 complex, GFH603 enhances the formation of KEAP1-CUL3 E3 ligase complex and thereby promotes NRF2 degradation. KEAP1 is a prevalent co-mutated gene in RAS-mutant tumors, and preclinical research demonstrated that GFH603 exerted potent antitumor efficacy both as a single agent and in combination with a Pan RAS inhibitor.
Unique molecular glue-like mechanism: enhancing KEAP1-CUL3 complex formation to induce NRF2 degradation
Persistent activation of the KEAP1 NRF2 pathway or elevated NRF2 expression is primarily driven by hotspot mutations of NFE2L2 (the gene encoding NRF2), KEAP1 mutations, or upstream oncogenic RAS signaling. Such aberrations may induce NFR2-driven therapeutic resistance and notably reduce the efficacy of chemotherapy, immunotherapy and targeted therapies.
NRF2 mutations occur at a high frequency in esophageal and lung squamous cell carcinomas, while KEAP1 represents a common co-mutated gene in KRAS in lung adenocarcinoma. RAS mutations are detected in approximately 90% of pancreatic cancer cases, with the NRF2 pathway broadly activated across this malignancy. In vitro studies indicated that GFH603 enhanced KEAP1 CUL3 complex activity in a concentration gradient dependent manner, thereby inducing NRF2 degradation and suppressing NRF2 driven cancer cell proliferation.
In vivo efficacy: GFH603 demonstrated potent antitumor activity as monotherapy and in combination with a Pan RAS inhibitor
In NRF2-mutant NSCLC models, GFH603 demonstrated superior and more durable antitumor efficacy versus VVD-130037, another KEAP1 CUL3 activator, at equivalent dose levels. In addition, in NSCLC models with concurrent KEAP1 and KRAS co-mutations, combination therapy of GFH603 with a Pan RAS inhibitor displayed obvious synergistic antitumor activity and achieved tumor regression.
In vitro research exhibited favorable druggability, with improved ADME/PK properties over VVD-130037
GFH603 exhibited low hERG liability and favorable oral bioavailability, together with superior ADME/PK properties relative to VVD-130037 in vitro. In addition, notable synergistic efficacy was observed following the combination of GFH603 with a Pan RAS inhibitor in KRAS/KEAP1 co-mutant cell lines. These findings demonstrated the candidate’s potential to overcome NRF2-driven resistance and supported the clinical rationale for combination strategy.
Hotspot mutations in NFE2L2, the gene encoding NRF2, are highly prevalent in esophageal and lung squamous cell carcinomas. In lung adenocarcinoma, KEAP1 represents a frequent co mutation alongside KRAS, while widespread activation of the NRF2 pathway is detected in pancreatic cancer. Sustained NRF2 overexpression drives broad resistance to standard-of-care therapies and previous studies suggested that concurrent KEAP1 mutations are linked to poor prognosis in RAS-mutant patients receiving standard-of-care treatments including immunotherapy.
As a molecular glue-like compound, GFH603 covalently binds to the Cys151 residue within the BTB domain of KEAP1, allosterically activating the protein to promote assembly of a functional KEAP1–CUL3 E3 ubiquitin ligase complex. That mechanism triggers the degradation of oncogenic NRF2, thereby suppressing tumor growth and enhancing the efficacy of multiple anti-cancer regimens.
With a focus on cutting-edge therapies, GenFleet Therapeutics is dedicated to serving significant unmet medical needs globally in oncology and immunology. Leveraging its deep understanding of disease biology and translational medicine, GenFleet has established a proprietary and fully integrated R&D system that yields a robust pipeline of multiple cutting-edge products with novel mechanisms and global IP.
Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates spanning small molecules and biologics. Its pipeline comprises numerous programs that have advanced to later-stage or pivotal clinical trials across China, the United States and Europe.
The company has set up a highly differentiated RAS-targeted matrix including selective and pan-RAS inhibitors of diverse molecular types, with most assets leading their categories in clinical progress in China or globally. In addition, the company has pioneered a series of first-in-class combination therapies based on dual-target synergistic mechanisms. By integrating clinical needs and insights, GenFleet is dedicated to expanding its portfolio into major therapeutic areas including pancreatic cancer, NSCLC, and cachexia. Furthermore, it's strengthening its commercial collaborative network through strategic out-licensing agreements or clinical cooperations with prestigious listed companies across the world.
