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. 2024 Nov 4;19(21):e202400081.
doi: 10.1002/cmdc.202400081. Epub 2024 Sep 16.

Coumarin-Based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors

Sravan K Jonnalagadda  1 , Ling Duan  2 , Louise F Dow  1 , Geetha P Boligala  3 , Elizabeth Kosmacek  4 , Kristyn McCoy  3 , Rebecca Oberley-Deegan  4   5 , Yashpal Singh Chhonker  6 , Darryl J Murry  5   6   7 , C Patrick Reynolds  3 , Barry J Maurer  3 , Trevor M Penning  2 , Paul C Trippier  1   5   7
Affiliations

Coumarin-Based Aldo-Keto Reductase Family 1C (AKR1C) 2 and 3 Inhibitors

Sravan K Jonnalagadda et al. ChemMedChem. .

Abstract

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.

Keywords: AKR1C2 Inhibitor; AKR1C3 Inhibitor; Drug Resistance; Leukemia; Prostate Cancer.

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Conflict of interest statement

Conflict of Interest

T.M.P. is a member if the Expert Panel for Research Institute for Fragrance Materials, is founder of Penzymes and a consultant for Propella and Sage Therapeutics.

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