The presence of a subpopulation of cancer stem-like cells (CSCs) expressing the surface glycoprotein CD133 and the enzyme Aldehyde Dehydrogenase (ALDH) within ovarian tumors has been associated with poorer cancer patient outcomes. ALDH+ cells show resistance to cisplatin, and engraftment of fewer than 500 CD133+/ALDH+ patient tumor cells is sufficient to establish tumors in mice, implicating these CSCs in recurrence metastasis following treatment in ovarian cancer. Administration of ALDH inhibitors can selectively deplete CD133+ cells and may represent a mechanistically novel treatment for ovarian cancer. While most evidence suggests ALDH1A1 is most critical for CSC function, the ideal selectivity profile among the 19 ALDH isoforms remains unclear. We have generated a library of analogs based on the ALDH1A1 inhibitor A39. Small structural changes have led to substantial improvements in 1A1 potency, widely varying selectivity profiles among the ALDH1A family, and several compounds capable of depleting CSCs in our cellular assay.

Development of cancer stem cell depleting ALDH1A selective inhibitors as potential therapeutics for ovarian cancer

253rd National Meeting (2017)

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