Evaluation of UCP1162, a potent propargyl-linked inhibitor of dihydrofolate reductase with potential application to cancer and autoimmune disease.

Autor: Ozcan Tezgin D; Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, United States., Kurkcu S; Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, United States., Si D; School of Pharmacy, University of Connecticut, Storrs, CT 06269, United States., Krucinska J; School of Pharmacy, University of Connecticut, Storrs, CT 06269, United States., Mosley A; Quercus Molecular Design, Farmington, CT 06032, United States., Mehta P; Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, United States., Babic I; CellarisBio, LLC, 9276 Scranton Rd, Suite 500, San Diego, CA 92121, United States., Nurmemmedov E; CellarisBio, LLC, 9276 Scranton Rd, Suite 500, San Diego, CA 92121, United States., Kuo A; Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, United States., He W; Flow Cytometry Core Facility, University of Connecticut, Storrs, CT 06269, United States., Nelson CE; Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, United States., Wright L; Quercus Molecular Design, Farmington, CT 06032, United States., Wright DL; School of Pharmacy, University of Connecticut, Storrs, CT 06269, United States; Quercus Molecular Design, Farmington, CT 06032, United States., Giardina C; Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, United States. Electronic address: charles.giardina@uconn.edu.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2024 Dec; Vol. 230 (Pt 3), pp. 116617. Date of Electronic Publication: 2024 Nov 09.
DOI: 10.1016/j.bcp.2024.116617
Abstrakt: Cellular resistance can limit the effectiveness of antifolate drugs for the treatment of cancer and autoimmune diseases. We examined the biochemical and cellular effects of a propargyl linked, non-classical antifolate UCP1162 that shows exceptional potency and resilience in the background of methotrexate resistance. UCP1162 inhibited the human DHFR enzyme with affinity and kinetics comparable to methotrexate (MTX). UCP1162 also inhibited cancer cell proliferation and bound cellular DHFR at low nanomolar concentrations. Leucovorin suppressed the cellular effects of UCP1162, consistent with UCP1162 working as an antifolate. Like other antifolates, UCP1162 reduced acute inflammation in mice and inhibited FLS cell growth and motility. Single cell RNA-seq showed that MTX and UCP1162 generated overlapping gene expression changes after a 48-hour exposure. However, while leukemia cells (CCRF-CEM) resistant to MTX could be readily selected, UCP1162-resistant cells could not be obtained. Long-term exposure to UCP1162 resulted in static culture expressing stem cell genes (CD34, ABCG2, ABCB1), adaptive genes (TCN2, CDKN1A), and genes that might serve as therapeutic targets (TPBG/5T4, TNFRSF10A, ACE). These findings suggest that UCP1162 is a unique tool for studying cellular responses to long-term antifolate treatment and holds promise as a lead compound capable of overcoming some forms of antifolate resistance.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DOT, SK, DS, JK, PM, IB, EN, WH, CEN, CG: no conflicts. AM, LW, DLW: Affiliated with Quercus Molecular Design, an early-stage biotechnology company developing antifolates.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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