Journal Article

(R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation

Ueshima, Taichi, Sanuki, Yusuke, Yamaguchi, Tomonori, Ureshino, Hiroshi, Takashima, Miyuki, Ichinohe, Tatsuo

2025

Overview

Hypomethylating agents combined with venetoclax (VEN), a BCL-2 inhibitor, represent a standard treatment strategy for patients with acute myeloid leukemia (AML). Although this combination is highly effective, acquired resistance commonly occurs. MCL-1, a BCL-2 family molecule, is frequently upregulated in VEN-resistant cells, playing a major role in VEN resistance. Previously, we demonstrated that ( R ) - WAC-224 is effective against AML with minimal cardiac toxicity. ( R )-WAC-224 combined with VEN demonstrated strong antileukemia effects on VEN-resistant AML cells overexpressing MCL-1 in vitro. Gene expression profiles revealed that ( R )-WAC-224 with VEN induced DNA damage pathways leading to cell apoptosis. ( R )-WAC-224 elicited caspase 3 activation, which cleaved MCL-1; this effect was reversed by a caspase inhibitor, thus overcoming VEN resistance. A combination of azacitidine (AZA), a hypomethylating agent, VEN, and ( R )-WAC-224 was highly effective against VEN-resistant AML in vivo without increasing toxicity. ( R )-WAC-224 exhibited antileukemia effects on VEN-resistant AML via MCL-1 downregulation in vitro and in vivo. The combination of AZA, VEN, and ( R )-WAC-224 may be a promising treatment strategy for patients with AML.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: (R)-WAC-224 / 631/136 / 631/154 / 631/67 / Acute myeloid leukemia / Animals / Anticancer quinolone / Antineoplastic Agents - pharmacology / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Apoptosis / Apoptosis - drug effects / Azacitidine - administration & dosage / Azacitidine - pharmacology / Bcl-2 protein / Bridged Bicyclo Compounds, Heterocyclic - pharmacology / Caspase inhibitors / Caspase-3 / Cell Line, Tumor / DNA damage / Down-regulation / Down-Regulation - drug effects / Drug Resistance, Neoplasm - drug effects / Gene expression / Humanities and Social Sciences / Humans / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - metabolism / Leukemia, Myeloid, Acute - pathology / MCL-1 / Mcl-1 protein / Mice / Molecules / multidisciplinary / Myeloid Cell Leukemia Sequence 1 Protein - genetics / Myeloid Cell Leukemia Sequence 1 Protein - metabolism / Quinolones / Science / Science (multidisciplinary) / Sulfonamides - administration & dosage / Sulfonamides - pharmacology / Toxicity / Venetoclax / Xenograft Model Antitumor Assays