AKR1C3 inhibitor(University of Pennsylvania)

Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity in vitro. None of the androstane derivatives have off-target affinity for the androgen receptor, based on a fluorescence assay in yeast cells. The X-ray structure of AKR1C3 in complex with the strongest inhibitor, a 17α-picolyl androstane with a C3-oxime modification, was determined at 1.7 Å resolution. Based on this crystal structure and molecular docking, inhibition of AKR1C3 by the 17α-picolyl or 17(E)-picolinylidene derivatives depends on interactions between the C3 modification and the NADP⁺ cofactor, while the C17α-picolyl or C17-picolinylidene group anchors the inhibitor to AKR1C3. Because one AKR1C3 inhibitor identified here was also previously reported to inhibit CYP17, it may be possible for future researchers to design dual AKR1C3/CYP17 inhibitors based on a steroid scaffold for potential treatment of advanced prostate cancers.

A series of 7‐substituted coumarin derivatives have been characterized as pan‐aldo‐keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7‐hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition. Coumarin amide 3 a possessed IC50 values of 50 nM and 90 nM for AKR1C3 and AKR1C2, respectively, and exhibits ‘drug‐like’ metabolic stability and half‐life in human and mouse liver microsomes and plasma. Compound 3 a was employed as a chemical tool to determine pan‐AKR1C2/3 inhibition effects both as a radiation sensitizer and as a potentiator of chemotherapy cytotoxicity. In contrast to previously reported pan‐AKR1C inhibitors, 3 a demonstrated no radiation sensitization effect in a radiation‐resistant prostate cancer cell line model. Pan‐AKR1C inhibition also did not potentiate the in vitro cytotoxicity of ABT‐737, daunorubicin or dexamethasone, in two patient‐derived T‐cell ALL and pre‐B‐cell ALL cell lines. In contrast, a highly selective AKR1C3 inhibitor, compound K90, enhanced the cytotoxicity of both ABT‐737 and daunorubicin in the T‐cell ALL cell line model. Thus, the inhibitory profile required to enhance chemotherapeutic cytotoxicity in leukemia may be AKR1C isoform and drug specific.