Biology subjects

Gardner, Z. S.

Publications and source records attributed to Gardner, Z. S..

3 recordsLinked to original sources

bioRxiv2025

Targeting tumor antioxidant pathways with novel GSTP1/M2 inhibitors for cancer treatment

Glutathione transferase (GSTP1 and GSTM2) are tractable targets for anticancer drug development. In this work, a series of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) based analogues were designed, synthesized, and evaluated both theoretically and experimentally as GSTP1 and GSTM2 inhibitors. Among the synthesized compounds, 3h showed selective inhibition toward GSTP1 while 5b showed selective inhibition of GSTM2. Compounds 5b and 5c exhibited stronger potency while compound 3h showed slightly lower potency against the tested cancer cells than its parent molecule NBDHEX. Comprehensive biological studies were conducted on the effect of 3h, 5b and 5c towards breast cancer MDA-MB-231 and pancreatic MiaPaCa-2 cell lines revealed that 3h, 5b and 5c could activate JNK pathway and induce cell apoptosis. Furthermore in vivo experiments using NSG mice demonstrated that 5b significantly reduced tumor growth when administered in combination with gemcitabine, effectively overcoming gemcitabine resistance in the MiaPaCa-2 cell model through targeted inhibition of GSTM2. These findings suggests that, 5b could become a promising candidate for further development as a potential antitumor agent in cancer therapy.

cancer biology↗

bioRxiv2025

Synthesis and biological evaluation of glutathione-responsive 2-alkoxycarbonyl allyl niclosamide prodrugs as anticancer agents

Reprogrammed mitochondrial metabolism is recognized as an important target for anticancer therapy. Niclosamide, an FDA approved anthelmintic agent with mitochondrial uncoupling activity, has shown promise as an anticancer agent. However, off target mitochondrial toxicity has rendered the utility of this agent at clinically effective doses. Here, we synthesize a variety of prodrugs on the niclosamide template based on the Baylis-Hillman (BH) reaction, with the hypothesis that niclosamide will be released upon the reaction with cellular nucleophiles, including thiols. Consistent with this hypothesis, the BH-prodrugs release the parent niclosamide in the presence of cysteine and glutathione, and the cancer cell proliferation inhibition properties of the lead candidates are retained when compared to the parent niclosamide. Mitochondrial respiration assays illustrate that niclosamide acutely uncouples the mitochondria, and the lead BH-prodrug 6b does not, providing evidence of this prodrug strategy in mitigating off target toxicities. In a dose escalation study, the lead candidate 6b is generally well tolerated in healthy mice as evidenced by zero mortality, normal grooming pattern, and normal weight gains. Finally, 6b exhibits 54% volume tumor growth inhibition properties in a syngraft model of breast cancer in mice. The studies herein provide a novel methodology for the application of BH prodrugs on the niclosamide template and the anticancer applications.

pharmacology and toxicology↗

bioRxiv2024

Development of fluoro-7-aminocarboxycoumarin-based mitochondrial pyruvate carrier inhibitors as anticancer agents

Reprogrammed metabolism of cancer cells offers a unique target for pharmacological intervention. In the current study, a series of novel and potentially metabolically stable fluoro-substituted aminocarboxycoumarin derivatives are evaluated for their mitochondrial pyruvate carrier (MPC) inhibition properties. Our studies indicate that the aminocarboxycoumarin template elicits potent MPC inhibitory characteristics, and specifically, structure activity relationship studies show that the N-methyl-N-benzyl structural template provides the optimal inhibitory capacity. Further respiratory experiments demonstrate that candidate compounds specifically inhibit pyruvate driven respiration without substantially affecting other metabolic fuels consistent with MPC inhibition. Further, computational homology and inhibitor docking studies illustrate that aminocarboxycoumarin binding characteristics are indicative of reversible covalent bonding with amino acids in the pyruvate binding domain. Epifluorescent microscopy experiments illustrated that FACC2 accumulates in the mitochondria to a similar extent as parent 7ACC2. Additionally, lead candidate aminocarboxycoumarin derivative D7 elicits cancer cell proliferation inhibition specifically in monocarboxylate transporter 1 (MCT1) expressing 4T1, consistent with its ability to accumulate intracellular lactate. In vivo tumor growth studies illustrate that D7 significantly reduces the tumor burden in two isogeneic murine cell lines 4T1 and 67nr. These studies provide novel MPC inhibitors with potential for anticancer applications.

cancer biology↗