Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Oncology

Background:

• Malate dehydrogenase 1 (MDH1) and MDH2 are crucial enzymes for lung cancer cell survival.
• Targeting MDH1/2 offers a potential therapeutic strategy for lung cancer treatment.

Purpose of the Study:

• To design and synthesize novel dual MDH1/2 inhibitors for lung cancer.
• To investigate the structure-activity relationship (SAR) of these inhibitors.
• To evaluate the efficacy of compound 50 in lung cancer cell lines.

Main Methods:

• Rational drug design and synthesis of dual MDH1/2 inhibitors.
• In vitro evaluation of growth inhibition in A549 and H460 lung cancer cell lines.
• Assessment of cellular ATP levels, HIF-1α accumulation, and target gene expression (GLUT1, PDK1, CD73).

Main Results:

• Compound 50, featuring a piperidine ring, showed enhanced growth inhibition against A549 and H460 cells compared to LW1497.
• Compound 50 dose-dependently reduced ATP content in A549 cells.
• Compound 50 suppressed HIF-1α accumulation and its target gene expression (GLUT1, PDK1) and inhibited HIF-1α-regulated CD73 expression under hypoxia.

Conclusions:

• Compound 50 exhibits significant anti-cancer effects in lung cancer cells by targeting MDH1/2 and inhibiting HIF-1α signaling.
• These findings support the potential of compound 50 as a next-generation dual MDH1/2 inhibitor for lung cancer therapy.