denifanstat (TVB-2640)

Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.

P1, N=40, Completed, Sagimet Biosciences Inc. | Active, not recruiting --> Completed

Despite these efforts, only a handful of inhibitors have entered clinical trials, such as 3-V Biosciences-2640 (denifanstat) and repurposed omeprazole, and none have received regulatory approval to date. Despite progress with novel and repurposed inhibitors, none have gained approval. This review critically examines past efforts, current challenges, and offers insights to guide future development of effective fatty acid synthase-targeting cancer therapeutics.

P3, N=240, Completed, Ascletis Pharmaceuticals Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Mar 2026 --> Nov 2025

P1, N=30, Recruiting, Weill Medical College of Cornell University | Trial completion date: Nov 2026 --> Jan 2029 | Trial primary completion date: Nov 2025 --> Jan 2027

Using an AI-driven prediction model and in vitro/in vivo assays, fatty acid synthase inhibitor TVB-2640 is identified as a potential therapeutic agent for disrupting metabolic vulnerability and suppressing NSCLC BMs. These findings provide novel insights into NET-dependent cellular interactions that sustain the pro-metastatic microenvironment underlying NSCLC BMs, offering robust development of novel metabolism-based therapeutic strategies to combat this lethal complication.

P3, N=480, Completed, Huashan Hospital, Fudan University; Huashan Hospital, Fudan University

P1, N=40, Active, not recruiting, Sagimet Biosciences Inc.

While by far, several FAS inhibitors, including denifanstat and omeprazole, have demonstrated beneficial effects in clinical trials, no candidate has been approved by the FDA. We concluded here that targeting FAS is a feasible strategy to overcome chemoresistance, although more interdisciplinary efforts are needed to identify a potent, specific, and bioavailable FAS inhibitor for clinical applications.

Novel modalities such as immunotherapy, gene editing, and multi-targeted therapies hold additional potential for fibrosis reversal. Continued translational efforts are critical to establish safe, effective, and accessible treatments for patients with liver fibrosis.

Denifanstat (TVB-2640), the first-in-class selective FASN inhibitor with favorable pharmacokinetic properties, has demonstrated robust antitumor activity in preclinical models and encouraging results in early-phase clinical studies. Clinical evidence suggests that FASN blockade not only impairs tumor growth but also potentiates the efficacy of existing treatments, including chemotherapy and targeted agents, thereby supporting its integration into combination regimens. Future clinical optimization will require the identification of predictive biomarkers to guide patient selection and treatment stratification.

Our findings reveal that KAT2B suppresses de novo lipogenesis by interfering with HDAC5-LSD1 complex assembly, and highlight the potential of FASN inhibitors as a therapeutic strategy for RCC patients with low KAT2B expression.