Potent and Highly Selective Aldo–Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia

Abstract

Aldo–keto reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F2α and PGF2α prostanoids that sustain the growth of myeloid precursors in the bone marrow. The enzyme is overexpressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). Moreover, AKR1C3 confers chemother-apeutic resistance to the anthracyclines: first-line agents for the treatment of leukemias. The highly homologous isoforms AKR1C1 and AKR1C2 inactivate 5α-dihydrotestosterone, and their inhibition would be undesirable. We report herein the identification of AKR1C3 inhibitors that demonstrate exquisite isoform selectivity for AKR1C3 over the other closely related isoforms to the order of >2800-fold. Biological evaluation of our isoform-selective inhibitors revealed a high degree of synergistic drug action in combination with the clinical leukemia therapeutics daunorubicin and cytarabine in in vitro cellular models of AML and primary patient-derived T-ALL cells. Our developed compounds exhibited >100-fold dose reduction index that results in complete resensitization of a daunorubicin-resistant AML cell line to the chemotherapeutic and >100-fold dose reduction of cytarabine in both AML cell lines and primary T-ALL cells.

Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors

“…Because daunorubicin remains the key drug component in conventional AML therapy, its inactivation by CREs constitutes another mechanism that might be responsible for diminished intracellular drug concentrations and lead to cellular resistance. We therefore screened the effect of CDKI on recombinant CREs isoforms that previously had been suggested to be related to cellular resistance to AML [23][24][25][26][27][28]. None of the tested drugs, however, achieved 50% inhibition in the applied 50 µM concentration.…”

“…Among those CREs reported to play a role in leukemia cells are CBR1, AKR1C3, AKR1A1, AKR1B1, and AKR1B10 [ 23 , 24 , 25 , 26 , 27 ]. Targeting daunorubicin inactivation therefore constitutes a modern pathway that could be exploited in order to prevent and overcome drug resistance [ 28 ].…”

Bruton’s Tyrosine Kinase Inhibitors Ibrutinib and Acalabrutinib Counteract Anthracycline Resistance in Cancer Cells Expressing AKR1C3

“…Therefore, there is a need to characterise AKR1C3-specific inhibitors with clinical relevance in human disease [ 14 ]. In this regard, several AKR1C3 inhibitors have been reported to re-sensitise anthracycline-resistant cancer cells to daunorubicin both in vitro and ex vivo [ 15 , 16 , 17 , 18 , 19 , 20 ]. This scope aims to decipher novel drugs for combination regimens with standard chemotherapeutics like anthracyclines, which can counteract the MDR incidence.…”

Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives Containing Benzoic Acid Group as Potential AKR1C3 Inhibitors

“…[30] Therefore, AKR1C3 is considered to be a vital therapeutic target in the treatment of CRPC through suppressing the final steps of intratumoral production of androgen. [27] Numerous AKR1C3 inhibitors with diverse scaffolds have been investigated for their enzyme inhibitory activity, such as steroids, [24] flavones, [31] jasmonates, [32] nonsteroidal anti-inflammatory drugs (NSAIDs, including Indomethacin analogs, [33,34] diarylpropionic acids, [35] and benzoic acid derivatives [36][37][38][39][40] ), cinnamic acid derivatives, [41] and some miscellaneous (SN33638, [42] ASP9521, [43] GTX-560, [30] morpholyl urea derivatives, [44] hydroxytriazole derivatives, [45] benzisoxazole derivatives, [46] berberine, [47] pyrazolopyran, [48] sulfonylureas [49] ). However, no specific AKR1C3 inhibitor has been successfully marketed.…”