Abstract A086: Development and Preclinical Evaluation of a Potent and Selective MASTL Inhibitor for Breast Cancer Therapy

Abstract MASTL is a mitotic kinase that inhibits PP2A via ENSA phosphorylation and is implicated in breast cancer progression. We developed MASTL inhibitor-3, a selective and metabolically stable small molecule with nanomolar potency (IC50 = 5 nM) and high specificity over other AGC kinases. Structure-based optimization of a quinazoline scaffold enhanced MASTL binding and suppressed ENSA phosphorylation, restoring PP2A activity. MASTL inhibitor-3 showed strong antiproliferative effects in MCF7, MDA-MB-231, BT549, and 4T1 breast cancer cells. It disrupted the MASTL–ENSA–Aurora A axis, leading to mitotic catastrophe and apoptosis. In a syngeneic 4T1 mouse model, it significantly inhibited tumor growth without detectable toxicity and outperformed a prior compound. These results highlight MASTL inhibitor-3 as a promising candidate for targeted breast cancer therapy. Citation Format: Ye-Hyun Kim, Ji-In Kim, Kwan-Young Jung, Jae-Sung Kim. Development and Preclinical Evaluation of a Potent and Selective MASTL Inhibitor for Breast Cancer Therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A086.