"Identification and design of cancer immunotherapy agents" Prof. Su-Ying Wu

Date

2016年3月2日 (水) 13:00 14:00

Location

Seminar Room C210, Center Bldg

Description

Integrated Open Systems Unit would like to invite you to the seminar by Prof. Su-Ying Wu.
"Identification and design of cancer immunotherapy agents: structure-based drug design of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) inhibitors"
 
[Speaker] 
Professor Su-Ying Wu
Investigator, National Health Research Institutes, Taiwan
Institute of Biotechnology and Pharmaceutical Research
 
[Title] 
Identification and design of cancer immunotherapy agents: structure-based drug design of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) inhibitors
 
[Abstract]

Cancer immunotherapy, a therapy to stimulate the patient’s immune system to attack the tumor cell, has provided a promising approach for the treatment of cancer. One of the mechanisms responsible for the escape of tumors from immune attack is through the tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). They are heme-containing enzymes that catalyze the initial and rate limiting step in the catabolism of tryptophan via the kynurenine pathway, leading to the formation of a series of biologically active metabolites. Through the catabolism of tryptophan, IDO/TDO inhibits the proliferation and differentiation of T cells, which are sensitive to the degradation of tryptophan and accumulation of tryptophan catabolites. A number of IDO inhibitors have been identified but only limited structural biology studies of IDO inhibitors are available to provide insights on the binding mechanism of IDO. We have recently solved the structures of IDO in complex with imidazoleisoindole derivatives, NLG919 (later named GDC-0919) analogues with potent activity. In this talk, structure-activity relationship, UV-spectra and structural biology studies of imidazoleisoindole derivaties will be presented and demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contributes to the great potency of this series of compounds.

As for the TDO inhibitors, only a few classes of TDO inhibitors have been reported to date. In this talk, I will present the application of the structure-based virtual screening approach to identify novel TDO inhibitors and further demonstrate the utility of the hit compounds by medicinal chemistry efforts in generating more potent TDO inhibitors. This resulted in the identification of substituted naphthotriazolediones as potent TDO inhibitors, making this series as potential for further development as therapeutic TDO-related targets.
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