<br/>AKR 1C3 (AKR) is a NADPH dependent enzyme which catalyzes steps on three different pathways of production of androgen hormones such as testosterone. AKR is an important drug target for prostate cancer (PC). Inhibitors of AKR which target the catalytic activity of AKR are used clinically to treat PC, but are ineffective against drug/chemical castration resistant PC (CRPC). CRPC can develop when tumor variants of AKR arise which directly activate the androgen receptor (AR) in the absence of the androgen. The nature of the altered AKR’s and the mechanism by which they directly activate AR are both poorly understood. One inhibitor of AKR, GTX560, inhibit both catalysis and AR activation, but no structure of this AKR/drug complex exists. We generated atomic resolution structural models of AKR-NADPH in the reduced and oxidized states, with and without a variety of inhibitors bound, including those that do and do not affect AR activation. We then used a combination of electrostatic analysis, docking, and pump-probe molecular dynamics in order to understand the mechanism of inhibition, to uncover possible allosteric pathways by which AKR activation of AR occurs and how GTX560 affect this allostery, with the aim of developing additional drug candidates against CRPC.

Searching for allosteric inhibitors of Aldo-keto reductase, a prostate cancer drug target

ACS Spring 2022

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