Meanwhile, compound 30t displayed good pharmacokinetic properties and favorable antitumor activity in vivo. Collectively, this study provides a novel compound for further development of anticancer drugs.

Additionally, compound 16e showed favorable pharmacokinetic characteristics and good antitumor efficacy in a SKOV3 xenograft model. Collectively, this study provides a promising candidate compound for the development of new therapeutics for cancer treatment.

P1, N=48, Recruiting, Epics Therapeutics

P1/2, N=188, Recruiting, STORM Therapeutics LTD

Finally, lower METTL3 expression in tumors correlated with improved sensitivity to anti-PD-1 immunotherapy in patients. Our findings revealed that METTL3-mediated m6A modification of PDL1 mRNA levels represents an epigenetic mechanism regulating anti-tumor immunity in GC, and inhibiting METTL3 during PD-1 mAb treatment reshaped the TME, thereby establishing a promising treatment approach for enhancing immunotherapy efficacy in GC patients.

P1, N=42, Completed, STORM Therapeutics LTD | Active, not recruiting --> Completed | Trial completion date: Mar 2025 --> Dec 2024 | Trial primary completion date: Dec 2024 --> Aug 2024

We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of EP652 as an in vivo proof-of-concept compound. EP652 potently inhibits the enzymatic activity of METTL3, has favorable PK parameters, and demonstrates efficacy in preclinical oncology models, indicating that pharmacological inhibition of METTL3 is a viable strategy for the treatment of liquid and solid tumors.

In conclusion, our study suggests that METTL3 regulates the stability of SLC7A11 mRNA in an m6A/IGF2BP2-dependent manner and the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 pathway, both of which require the m6A methyltransferase activity of METTL3. METTL3 or IGF2BP2 may be promising targets for radiotherapy of HCC.

Silencing METTL3 promoted apoptosis of CRC cells and increased their sensitivity to OXA by inhibiting the Wnt/β‑catenin signaling pathway. Huaier downregulated the expression of METTL3, thereby promoting apoptosis of drug‑resistant CRC cells and increasing their sensitivity to OXA by inhibiting the Wnt/β‑catenin signaling pathway.

Combining the hydrogel with CAR-NK cell therapy significantly reduced CRC recurrence in vivo. Overall, our study reveals the crucial role of METTL3 in CRC recurrence and proposes a promising, multimodal strategy using STM2457-loaded hydrogel and CAR-NK cells for enhanced therapeutic efficacy.

Salus IRB, Protocol STC15-22101. All patients gave informed consent before participation.

Among them, compound C3 showed significant inhibitory activity on METTL3, and further molecular dynamics simulations were performed to provide more details about the binding conformation. Overall, our research demonstrates the effectiveness of hybrid virtual algorithms, which is of great significance for understanding the biological functions of METTL3 and developing treatment methods for related diseases.