lonidamine

Lonidamine (Diclondazolic Acid) is an indazole carboxylic acid derivative, principally inhibiting aerobic glycolytic activity, by its effect on mitochondrially-bound hexokinase (HK).

Lon-TK is a glycolysis inhibitor of LTB, linked with a linker conjugate. LTB is an intelligent responsive prodrug, comprised of Lonidamine (Lon) and a PD-L1 inhibitor (BMS-1), which are connected through a thioketal linkage. It effectively inhibits glycolytic metabolism in tumor cells and blocks the PD-1 PD-L1 immune escape pathway. Lon-TK holds potential for use in photodynamic-enhanced immunotherapy research.

LTB is a prodrug formed through the conjugation of the glycolysis inhibitor (Lonidamine) and the PD1 PDL1 blocker (BMS-1) via a thioketal bond. LTB can encapsulate the photosensitizer Chlorin e6 (Ce6), constructing a co-delivery photodynamic nanoplatfform through self-assembly (LTB-6 NPs).

Chol-CTPP, a ligand with a dual targeting effect on the blood-brain barrier (BBB) and glioma cells, serves as the precursor to Lip-CTPP when combined with another mitochondria-targeting ligand (Chol-TPP). Lip-CTPP emerges as a potential carrier facilitating the collaborative anti-glioma efficacy of doxorubicin (DOX) and lonidamine (LND). It significantly enhances the inhibition of tumor cell proliferation, migration, and invasion, promotes apoptosis and necrosis, and disrupts mitochondrial function [1].

C-02, a proteolysis-targeting chimera (PROTAC) that combines the hexokinase inhibitor lonidamine with the cereblon ligand thalidomide, effectively induces the degradation of hexokinase 2 in 786-O and PANC-1 cells at a concentration of 20 µM. This compound exhibits cytotoxicity to a range of cancer cells, including 786-O, 4T1, PANC-1, HGC-27, and MCF-7, with IC50 values of 34.07 µM, 5.08 µM, 31.53 µM, 6.11 µM, and 21.65 µM, respectively. Additionally, at 20 µM, C-02 diminishes both the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in 4T1 cells, suggesting a suppression of glycolysis and mitochondrial damage. In vivo studies reveal that at a dosage of 50 mg/kg, C-02 not only reduces tumor volume but also promotes intratumoral cytokine accumulation and triggers pyroptosis in a 4T1 murine mammary carcinoma model.

Mito-LND (Mito-Loidamine) is an orally active and mitochondria-targeted inhibitor of oxidative phosphorylation.