Arzneimittelkombinationen von Bcl-Xl-Hemmern zur Behandlung von Krebs

Details

Veröffentlichungs-Nr.

EP4714447

Anmeldetag

18. September 2024

Veröffentlichung

25. März 2026

Rechtsraum

EP

Abstract

The invention covers a novel combination therapy for the treatment of cancer, preferably of colorectal cancer. The inventors identified Manidipine-2HCl as a selective inhibitor of UGT8, a key enzyme in the synthesis of sulfatides. In agreement, lipidomic analysis indicated that sulfatides are strongly reduced in colorectal cancer cells upon treatment with Manidipine-2HCl. Intriguingly, this reduction led to severe mitochondrial swelling and a strong synergism with BH3 mimetics targeting BCL-XL, leading to the activation of mitochondria-dependent apoptosis. The inventors demonstrated that mechanistically, Manidipine-2HCl enhanced mitochondrial BAX localization in a sulfatide-dependent fashion, facilitating its activation by BH3 mimetics. This disclosure relates to a method of treating a patient suffering from cancer with a combination therapy comprising a BCI-XL inhibitor and a UGT8 inhibitor. This disclosure also relates to uses of such combination for preparation of a medicament for the treatment of a cancer; methods of treating a cancer in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combination; pharmaceutical compositions comprising such combination and commercial packages thereto.

Anmelder

Firma

Stichting Amsterdam UMC

Land

🇳🇱 Niederlande