Potent and Highly Selective Aldo–Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T‑Cell Acute Lymphoblastic Leukemia
dataset
posted on 2019-03-05, 00:00 authored by Kshitij Verma, Tianzhu Zang, Trevor M. Penning, Paul C. TrippierAldo–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 chemotherapeutic 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.
