Aldo-Keto Reductase Family 1 Member B10 as a Therapeutic Frontier: Advances in Inhibitor Design and Multimodal
Jikuan Shao1, Xiaolong Wang1, Can Guo1
1School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
None:
Aldo-keto reductase 1B10 (AKR1B10), a key member of the aldehyde-ketone reductase superfamily, plays crucial roles in tumorigenesis, chemotherapy resistance, and metabolic regulation. However, the clinical translation of its inhibitors has been persistently hindered by off-target toxicities arising from highly homologous enzymes and severe competition from intracellular substrates. This review critically summarizes the paradigm shift in AKR1B10-targeted drug discovery. From a structural pharmacology perspective, we systematically elucidate how inhibitor design has evolved from classical anion-binding pocket (ABP) anchoring to pocket-specific designs that exploit the topological differences of subpockets (LAS/SP) to overcome subtype selectivity barriers. Furthermore, to bypass the inherent limitations of reversible competitive inhibition, we prospectively explore next-generation therapeutic modalities, including targeted protein degradation (PROTACs), covalent modifiers, and small molecule-drug conjugates (SMDCs), alongside multitarget combination regimens aimed at systematically dismantling tumor resistance networks. Ultimately, this review aims to provide breakthrough insights to overcome current clinical bottlenecks, providing a reference for the future development of novel, highly efficacious precision oncology therapeutics.
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