Comparable TXNIP-inhibiting, anti-apoptotic and anti-diabetic effects of TIX100 and its individual enantiomers
Abstract
Thioredoxin-interacting protein (TXNIP) is a stress-responsive gene that is upregulated by endoplasmic reticulum stress, cytokine toxicity and high glucose and pathologically elevated in diabetes. In pancreatic islets this leads to dysfunction and promotes beta cell apoptosis thereby contributing to disease progression. On the other hand, targeting inhibition of beta cell TXNIP has emerged as a promising, novel, therapeutic approach for type 1 diabetes. Indeed, genetic deletion or pharmacological inhibition of TXNIP protect against beta cell destruction and diabetes. TIX100 is an oral, small molecule TXNIP inhibitor currently completing Phase 1 clinical trials. Structurally, TIX100 is a chiral drug and thus far has been used as a racemate. Even though the effects of a racemate and its isolated enantiomers can vary greatly providing potential advantages for drug development, the properties of the individual TIX100 enantiomers have remained unknown. The aim of the current studies was therefore to elucidate how the individual TIX100 enantiomers compare to the TIX100 racemate. Using in vitro and in vivo studies in diabetic mice, we found that the TIX100 racemate and its individual R- and S-enantiomers are stable, have similar metabolic profiles and are comparable in potency and effectiveness of lowering beta cell TXNIP, promoting beta cell survival and function and protecting against beta cell destruction-induced diabetes. Taken together with the extensive preclinical work and the Phase 1 clinical trials using the TIX100 racemate that have not revealed any relevant safety concerns, no rationale for pursuing a single enantiomer for further diabetes drug development seems to exist in the case of TIX100.
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BibTeX
@article{jing2026comparable,
title = {{Comparable TXNIP-inhibiting, anti-apoptotic and anti-diabetic effects of TIX100 and its individual enantiomers}},
author = {Gu Jing and Junqin Chen and Guanlan Xu and Anath Shalev},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1992873},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1992873},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Comparable TXNIP-inhibiting, anti-apoptotic and anti-diabetic effects of TIX100 and its individual enantiomers
AU - Gu Jing
AU - Junqin Chen
AU - Guanlan Xu
AU - Anath Shalev
PY - 2026
DA - 2026/11/06
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1992873
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1992873
AB - Thioredoxin-interacting protein (TXNIP) is a stress-responsive gene that is upregulated by endoplasmic reticulum stress, cytokine toxicity and high glucose and pathologically elevated in diabetes. In pancreatic islets this leads to dysfunction and promotes beta cell apoptosis thereby contributing to disease progression. On the other hand, targeting inhibition of beta cell TXNIP has emerged as a promising, novel, therapeutic approach for type 1 diabetes. Indeed, genetic deletion or pharmacological inhibition of TXNIP protect against beta cell destruction and diabetes. TIX100 is an oral, small molecule TXNIP inhibitor currently completing Phase 1 clinical trials. Structurally, TIX100 is a chiral drug and thus far has been used as a racemate. Even though the effects of a racemate and its isolated enantiomers can vary greatly providing potential advantages for drug development, the properties of the individual TIX100 enantiomers have remained unknown. The aim of the current studies was therefore to elucidate how the individual TIX100 enantiomers compare to the TIX100 racemate. Using in vitro and in vivo studies in diabetic mice, we found that the TIX100 racemate and its individual R- and S-enantiomers are stable, have similar metabolic profiles and are comparable in potency and effectiveness of lowering beta cell TXNIP, promoting beta cell survival and function and protecting against beta cell destruction-induced diabetes. Taken together with the extensive preclinical work and the Phase 1 clinical trials using the TIX100 racemate that have not revealed any relevant safety concerns, no rationale for pursuing a single enantiomer for further diabetes drug development seems to exist in the case of TIX100.
SN - 1663-9812
ER -