Aldehyde dehydrogenases as drug targets for cancer: SAR and structural biology aspects for inhibitor design

Aldehydes are organic compounds containing a carbonyl group found exogenously or produced by normal metabolic processes and their accumulation can lead to toxicity if not cleared. Aldehyde dehydrogenases (ALDHs) are NAD(P)⁺-dependent enzymes that catalyze the oxidation of such aldehydes and prevent their accumulation. Along with this primary detoxification function, the known 19 human isoforms of ALDHs, which act on different substrates, are also involved in various physiological and developmental processes. Functional alterations of ALDHs via mutations or expression levels cause various disease conditions, including many different cancer types like lung, ovarian, etc. These properties make this family of enzymes an ideal therapeutic and prognostic target for drug development. However, sequence similarities between the ALDH isoforms force the need to design inhibitors for a specific isoform using the differences in the substrate-binding sites of each protein. This has resulted in developing isoform-specific inhibitors, especially for ALDH1A1, ALDH2, and ALDH3A1, which are implicated in various cancers. In this review, we briefly outline the functional roles of the different isoforms of the ALDH family members, their role in cancer and discuss the various selective inhibitors that have been developed for the ALDH1A1 and ALDH3A1 enzymes, along with a detailed examination of the respective structure-activity relationship (SAR) studies available. From the available SAR and structural biology data, insights into the functional groups and interactions necessary to develop selective inhibitors for ALDH1A1 and ALDH3A1 are highlighted, which can act as a guide for developing more potent and selective inhibitors of ALDH isoforms.