Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1

Abstract

Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-α (HIF-α) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-α. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-α/HRE transcriptional activity.

Prolyl Hydroxylase Domain Protein Inhibitor Not Harboring a 2-Oxoglutarate Scaffold Protects against Hypoxic Stress

“…To stabilize the HIF-α protein with small chemical compounds, the inhibition of PHD enzyme activities has been a major point of focus. PHDs require ferrous ions (Fe 2+ ), 2-oxoglutarate (2-OG), and ascorbic acid to hydroxylate HIF-α ODD. , Competitive inhibitors derived from the 2-OG structure have been synthesized ,,− and developed as new types of therapeutic compounds for renal anemia. − FG4592 (roxadustat), for example, was recently approved as a therapeutic compound for anemia associated with chronic kidney disease (CKD). , However, it is estimated that more than 60 proteins have 2-OG as a cofactor. ,, Therefore, the VHL inhibitor , and FIH inhibitor − have been developed as inhibitors targeting compounds other than PHDs without mimicking 2-OG; however, they have not yet been approved. Although a large number of PHD inhibitors have been reported, there are still several HIF activators that do not harbor the 2-OG scaffold.…”

Identification of Novel Direct Small-Molecule Inhibitors against HIF-2A using Structure-based Virtual Screening and Molecular Dynamics Simulation

“…Long exposure of CCRCC cell-lines to PT2385 have been reported to induce cellular resistance against the treatment (61). Indole analogs, Thiophene and Tricyclic derivatives are other class of small-molecule inhibitors that directly target HIF2A subunit and have been shown to successfully prevent HIF2A activity in 786-Ocells (62)(63)(64). Inhibition of the HIF2A subunit was a treatment option not only for specific types of cancers, but also other diseases, such as muscle injury, and disorders related to iron overload as well (43,(65)(66)(67)(68)(69).…”

Inhibition of the Oxygen-Sensing Asparaginyl Hydroxylase Factor Inhibiting Hypoxia-Inducible Factor: A Potential Hypoxia Response Modulating Strategy

“…In 2008, Tsujita and co-workers reported a series of furan-and thiophene-2-carbonyl amino acid derivatives derived from computational studies with the potential to inhibit FIH. 99 Although biochemical studies were not reported (and need to be done to validate direct FIH inhibition), their results with engineered reporter cells suggest this series may be at least partially selective for FIH (Figure 13A). 15 is reported not to upregulate HIF-α under normoxic conditions, suggesting it does not inhibit the PHDs.…”