Discovery of a first-in-class benzopyrane-derived anticancer agent
possessing a dual inhibition of thioredoxin and glutathione reductases
Abstract
Background and Purpose: The dual inhibition of thioredoxin reductase
(TrxR) and glutathione reductase (GSHR) has emerged as a promising
approach for the treatment of cancer and for promoting the defense
mechanism by the immune system. In a previous report, we described a
modular and novel strategy for the synthesis of a small molecule
library. Here, we aim to discover a novel benzopyrane derivative that
possesses a multitarget anticancer mechanism of action. Experimental
Approach: The anticancer effect of SIMR1281 was evaluated in vitro to
determine its effect on GSHR, TrxR, mitochondrial metabolism, DNA
damage, cell cycle progression, and induction of apoptois. In addition,
SIMR1281 was evaluated in vivo for its safety and in xenograft mice
model. Key Results: SIMR1281 strongly inhibits GSHR while moderately
inhibits TrxR. It inhibits cell proliferation of various cancers and
mediates the induction of DNA damage machinery. SIMR1281, perturbs cell
cycle, inactivates Ras/ERK and PI3K/Akt pathways. Furthermore, SIMR1281
induces apoptosis and strongly attenuates cell survival machinery.
SIMR1281 significantly reduces tumor volume in a xenograft model while
maintaining a high in vivo safety profile. Conclusion and Implications:
Our findings demonestrate that SIMR1281 possesses a promising
multitarget anticancer activity in vitro and in vivo against multiple
types of cancers while maintaining a high in vivo safety profile. This
unique activity of SIMR1281 represents an innovative strategy for the
treatment of various types of cancers and places this compound in a
privileged position as a potential clinical drug candidate.