A Novel Benzopyrane Derivative Targeting Cancer Cell Metabolic and Survival Pathways

SIMPLE SUMMARY: This work aimed to illustrate the anticancer mechanism of action of a novel benzopyrane derivative as a potential anticancer lead compound. The anticancer activity of SIMR1281 against a panel of cancer cell lines was characterized. The effects of SIMR1281 on glutathione reductase (GSHR), thioredoxin reductases (TrxR), mitochondrial metabolism, DNA damage, cell cycle progression, and apoptosis induction were determined. SIMR1281 was evaluated in vivo for its safety and efficacy. SIMR1281 strongly inhibited GSHR while it moderately inhibited TrxR and modulated the mitochondrial function. It inhibited cell proliferation by inducing DNA damage, perturbations of the cell cycle, and inactivation of Ras/ERK and PI3K/Akt pathways, consequently leading to apoptosis. SIMR1281 significantly reduced tumor volume in a tumor xenograft model while maintaining a high safety. These findings support developing SIMR1281 in preclinical and clinical settings as it represents a potential lead compound for the treatment of cancer. ABSTRACT: (1) Background: Today, the discovery of novel anticancer agents with multitarget effects and high safety margins represents a high challenge. Drug discovery efforts indicated that benzopyrane scaffolds possess a wide range of pharmacological activities. This spurs on building a skeletally diverse library of benzopyranes to identify an anticancer lead drug candidate. Here, we aim to characterize the anticancer effect of a novel benzopyrane derivative, aiming to develop a promising clinical anticancer candidate. (2) Methods: The anticancer effect of SIMR1281 against a panel of cancer cell lines was tested. In vitro assays were performed to determine the effect of SIMR1281 on GSHR, TrxR, mitochondrial metabolism, DNA damage, cell cycle progression, and the induction of apoptosis. Additionally, SIMR1281 was evaluated in vivo for its safety and in a xenograft mice model. (3) Results: SIMR1281 strongly inhibits GSHR while it moderately inhibits TrxR and modulates the mitochondrial metabolism. SIMR1281 inhibits the cell proliferation of various cancers. The antiproliferative activity of SIMR1281 was mediated through the induction of DNA damage, perturbations in the cell cycle, and the inactivation of Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281 induced apoptosis and attenuated cell survival machinery. In addition, SIMR1281 reduced the tumor volume in a xenograft model while maintaining a high in vivo safety profile at a high dose. (4) Conclusions: Our findings demonstrate the anticancer multitarget effect of SIMR1281, including the dual inhibition of glutathione and thioredoxin reductases. These findings support the development of SIMR1281 in preclinical and clinical settings, as it represents a potential lead compound for the treatment of cancer.