Abstract

Aldo-keto reductase 1B10 (AKR1B10) is a human enzyme that catalyzes the NADPH-dependent reduction of several different carbonyl compounds to the corresponding alcohols. Under physiological conditions, AKR1B10 is expressed mainly in the gastrointestinal tract, where it can detoxify reactive carbonyl compounds derived from dietary sources and xenobiotics. AKR1B10 is highly expressed in several cancers and precancerous conditions, proving to be crucially implicated in carcinogenesis and to function as a prognostic indicator of tumor development. Moreover, AKR1B10 up-regulation is strictly related to acquired resistance to known anticancer drugs. High levels of this enzyme are also correlated to the pathogenesis of noncancerous diseases, such as skin pathologies and COVID-19 complications. Therefore, in the last two decades, AKR1B10 has attracted interest as a novel target for agents able to fight both cancer and chemoresistance, and here, it is explored from a medicinal chemistry perspective.

Abstract

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (gliflozins) represent the most recently approved class of oral antidiabetic drugs. SGLT-2 overexpression in diabetic patients contributes significantly to hyperglycemia and related complications. Therefore, SGLT-2 became a highly interesting therapeutic target, culminating in the approval for clinical use of dapagliflozin and analogues in the past decade. Gliflozins improve glycemic control through a novel insulin-independent mechanism of action and, moreover, exhibit significant cardiorenal protective effects in both diabetic and nondiabetic subjects. Therefore, gliflozins have received increasing attention, prompting extensive structure-activity relationship studies and optimization approaches. The discovery that intestinal SGLT-1 inhibition can provide a novel opportunity to control hyperglycemia, through a multifactorial mechanism, recently encouraged the design of low adsorbable inhibitors selectively directed to the intestinal SGLT-1 subtype as well as of dual SGLT-1/SGLT-2 inhibitors, representing a compelling strategy to identify new antidiabetic drug candidates.