Aldo-keto reductase 1 C3 (AKR1C3) is overexpressed in a range of leukemias, prostate and other
cancers, where it functions to regulate myeloid and lymphoblast cell differentiation, proliferation and apoptosis,
synthesize potent androgens that drive cancer progression and contributes to drug resistance across several
classes of chemotherapeutic. Our preliminary results have identified the most selective AKR1C3 isoform
inhibitors ever reported. These inhibitors provide significant potentiation effect (up to 208-fold) across four
classes of chemotherapeutics in six different acute myeloid leukemia (AML) and castration-resistant prostate
cancer (CRPC) cell lines, and in primary relapsed patient-derived T-cell acute lymphoblastic leukemia (T-ALL)
cells. We hypothesize that isoform selective inhibition of AKR1C3 by rationally designed small molecules will
have significant effect to potentiate the cytotoxicity of clinical chemotherapeutics across a range of
malignancies. The goal of this proposal is to optimize this new scaffold for greater potency, stability and
potentiation effect, to characterize the role of AKR1C3 in cancer, and to validate the AKR1C3 isoform as a
target for the treatment of AML, T-ALL and CRPC.
The overall impact of this proposal is the in vivo proof-of-concept that isoform selective AKR1C3
inhibitors enhance the therapeutic window of clinical chemotherapeutics; enhancing efficacy, countering
resistance and reducing side effects. Thus enabling the use of clinically approved anticancer agents in
vulnerable pediatric and geriatric patients.