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

Kshitij Verma, Tianzhu Zang, Trevor M. Penning, Paul C. Trippier

Research output: Contribution to journalArticle

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Abstract

Aldo-keto reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F and PGF 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.

Original languageEnglish (US)
Pages (from-to)3590-3616
Number of pages27
JournalJournal of Medicinal Chemistry
Volume62
Issue number7
DOIs
StatePublished - Apr 11 2019

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Protein Isoforms
Daunorubicin
Dinoprost
Cytarabine
Myeloid Cells
Leukemia
Cell Line
Dihydrotestosterone
Anthracyclines
Prostaglandins
Bone Marrow
carbonyl reductase (NADPH)
Enzymes
Therapeutics
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Potent and Highly Selective Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia. / Verma, Kshitij; Zang, Tianzhu; Penning, Trevor M.; Trippier, Paul C.

In: Journal of Medicinal Chemistry, Vol. 62, No. 7, 11.04.2019, p. 3590-3616.

Research output: Contribution to journalArticle

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