Identification of β‑Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B‑Cell Lymphoma

The
treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the
urgent unmet medical needs because it is the most resistant DLBCL
subtype to current therapies eagerly awaiting effective therapeutic
strategies. Recently, the paracaspase MALT1 has emerged as a promising
therapeutic target for the treatment of ABC-DLBCL. Herein, we report
a new class of MALT1 inhibitors developed by high-throughput screening
and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone
series inhibited MALT1 activity but suffered from poor cellular activity.
The extensive pharmacophore search led to the discovery of structurally
similar β-lapachone that is a direct inhibitor of MALT1 and
possesses favorable physicochemical properties. Molecular simulation
studies suggested the possibility of the formation of a covalent bond
between MALT1 and β-lapachone, which was corroborated by experimental
wash-out studies. Inspired by this, we explored the structure–activity
relationships by incorporating electron-withdrawing substituents at
C8 position of β-lapachone. These MALT1 inhibitors exhibited
potent antiproliferative activity to OCI-LY3 cell line and inhibited
the cleavage of CYLD mediated MALT1.