Targeting Cancer Stem Cell Metabolism via Isoform-specific ALDH1B1 and ALDH1A3 Inhibitors

Colorectal cancer affects 1.4 million new patients annually, with existing treatments often ineffective. A key factor in treatment resistance is high aldehyde dehydrogenase activity, which undermines several chemotherapies. Stanford University's Chen Lab has developed two groundbreaking classes of inhibitors that selectively target specific aldehyde dehydrogenase isoforms.

These imidazolium and guanidine-based compounds are:

• The first selective inhibitors of ALDH1B1, an enzyme essential for cancer stem cell survival in colorectal and pancreatic cancers
• Selective ALDH1A3 inhibitors targeting breast cancer and melanoma

Recent Chen Lab advancements demonstrate:

• Nanomolar potency against cancer spheroids
• Nearly 100-fold selectivity for specific ALDH isoforms
• Enhanced metabolic stability
• Improved pharmacokinetic properties (reduced clearance, higher maximum concentration) in mice

This approach represents a shift from targeting rapid cell division to addressing the metabolic pathways that sustain cancer stem cells. These inhibitors have significant therapeutic potential for combination therapies and other drug-conjugate applications for a broad range of cancers, potentially improving long-term outcomes for cancer patients.

Stage of Development
Research in vivo