Discovery of METTL3 inhibitor C191-0266 as a leukemia therapeutic through targeted modulation of protective autophagy.

To develop novel anti-leukemia therapies, a CNN model identified C191-0266 targeting METTL3, which exhibited potent anti-leukemia activity. It inhibited the proliferation of OCI-AML3, MOLM-13, and THP-1 cell lines with IC50 values of 16.91 μM, 19.01 μM, and 24.99 μM respectively, showed strong METTL3 binding (KD = 7.28 μM) and enzymatic inhibition (IC50 = 7.639 μM), enhanced Ara-C's cytotoxicity by suppressing Ara-C-induced protective autophagy, maintained stable binding to METTL3, regulated the NF-κB pathway to inhibit TNF-α overexpression in Ara-C-resistant cell lines, and had favorable pharmacokinetics and safety profiles via ADME assessments, thus holding promise as an anti-leukemia drug candidate.