Molidustat targets a synthetic lethal vulnerability in APC-mutant colorectal cancer through GSTP1 and PHD2 co-inhibition.

Molidustat, a PHD2 inhibitor, induces cell death in human APC-mutant colorectal cancer cells via off-target inhibition of GSTP1, linked to a GSTP1–PHD2 synthetic lethal interaction.

• Why it matters: APC mutations create metabolic and stress adaptation demands that may expose vulnerabilities, but PHD inhibitor mechanisms and off-target effects in CRC are unclear.
• What they did: The study used thermal proteome profiling and chemical proteomics to identify GSTP1 as a Molidustat off-target, then tested effects of PHD2 loss versus combined PHD2 and GSTP1 loss, including integrated proteomics and metabolomics.
• The result: Combined loss of PHD2 and GSTP1 produced synergistic proteomic changes tied to cell-cycle suppression and apoptotic signalling, and APC-mutant mouse organoids showed selective Molidustat sensitivity not reproduced by hydroxylase inhibition alone.

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