DUAL INHIBITORS OF INDOLEAMINE-2,3-DIOXYGENASE (IDO) AND TRYPTOPHAN-2,3-DIOXYGENASE (TDO) AS ANTI-TUMOR IMMUNE MODULATORS

Document Type : Original Article

Authors

1 Pharmaceutical Medicinal Chemistry& Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.

2 Pharmaceutical Medicinal Chemistry& Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt

Abstract

Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are enzymes that catalyze the rate-limiting step of the kynurenine pathway. Recent literature reports IDO and TDO upregulation in tumor cells leading to L-tryptophan depletion and accumulation of tryptophan metabolites. This process represents an essential mechanism for tumor-induced immunosuppression. Following the failure of Epacadostat, an IDO inhibitor, in phase 3 clinical trials, numerous studies have shifted to a dual inhibition scheme to overcome the compensation mechanism linked to TDO. Therefore, the dual inhibition of IDO and TDO using a single molecule emerges as a highly promising therapeutic approach. This comprehensive review aims to discuss the successful scaffolds of reported dual inhibitors and their inhibitory values against both enzymes. The reported active compounds have the potential to form a novel chemical class of anti-tumor immune modulator drugs.

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