Drug development targeting oligomerization of human aldehyde dehydrogenase ALDH1A3, a cancer stem cell marker

The primary objective of oncologic therapy is the suppression of tumor proliferation and, ultimately, the eradication of malignant cells, predominantly through surgical resection and chemotherapeutic agents. A critical limitation in this approach is the high proliferative capacity of tumor cells, which facilitates the emergence of heterogeneous subpopulations capable of acquiring chemoresistance. This resistance compromises therapeutic efficacy and increases collateral damage to non-malignant tissues. A promising strategy to overcome chemoresistance involves the co-administration of cytotoxic agents with compounds that inhibit enzymes responsible for drug inactivation. Aldehyde dehydrogenase 1A3 (ALDH1A3) is a homotetrameric enzyme physiologically involved in the detoxification of xenobiotics. However, its aberrant overexpression has been implicated in several malignancies, where it contributes to chemoresistance by enhancing drug metabolism and cellular survival pathways. This study investigates the potential of selected ALDH1A3 inhibitors to disrupt its oligomeric assembly, a mechanism that could attenuate enzymatic activity and restore chemosensitivity. The inhibitors, previously validated in vitro, in cell culture, and in in vivo models, will be assessed for their capacity to interfere with ALDH1A3 tetramer formation using Small-Angle X-ray Scattering (SAXS). Structural validation of oligomeric disruption by SAXS will inform the rational design of next-generation ALDH1A3 inhibitors with enhanced potency and selectivity. Targeting ALDH1A3 oligomerization represents a novel and unexplored therapeutic avenue in the modulation of drug resistance in cancer.