Drug intelligence / Profile preview

TDZ6

Development stage: Preclinical
Lead developer: Università di Padova
Modality: Small Molecules
Administration: Intraperitoneal

Overview

TDZ6 is a novel thioridazine (TDZ) analogue developed to target lysine methyltransferase 2A (KMT2A)-rearranged pediatric acute myeloid leukemia (AML), specifically those harboring the t(6;11) KMT2A::AFDN (MLL-AF6) fusion. Chemically modified to increase branching and polarity, TDZ6 overcomes the high blood-brain barrier permeability and cardiotoxicity associated with thioridazine while maintaining potent anti-leukemic activity. It acts by binding to the S100A8/A9-ANXA6 complex, triggering cytoskeletal remodeling, calcium influx, and mitochondrial depolarization, which leads to apoptosis in leukemia cells. TDZ6 has demonstrated synergistic efficacy when combined with the BCL-2 inhibitor venetoclax in preclinical models of KMT2A-rearranged AML.

Targets

ANXA6S100A8 (S100 calcium-binding protein A8)S100A9 (Myeloid-related protein 14)

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