Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form

被引：159

作者：

Nelp, Micah T. ^{[1
]}

Kates, Patrick A. ^{[1
]}

Hunt, John T. ^{[2
]}

Newitt, John A. ^{[3
]}

Balog, Aaron ^{[4
]}

Maley, Derrick ^{[2
]}

Zhu, Xiao ^{[3
]}

Abell, Lynn ^{[5
]}

Allentoff, Alban ^{[6
]}

Borzilleri, Robert ^{[4
]}

Lewis, Hal A. ^{[3
]}

Lin, Zeyu ^{[5
]}

Seitz, Steven P. ^{[4
]}

Yan, Chunhong ^{[3
]}

Groves, John T. ^{[1
]}

机构：

[1] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA

[2] Bristol Myers Squibb Co, Immunooncol Biol, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Co, Mol Discovery Technol, Princeton, NJ 08543 USA

[4] Bristol Myers Squibb Co, Dept Discovery Chem, Princeton, NJ 08543 USA

[5] Bristol Myers Squibb Co, Leads Discovery & Optimizat, Princeton, NJ 08543 USA

[6] Bristol Myers Squibb Co, Dept Radiochem, Princeton, NJ 08543 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 13期

关键词：

IDO1; heme; cancer; kynurenine; SOLUBLE GUANYLYL CYCLASE; 1; IDO1; INHIBITORS; TRYPTOPHAN CATABOLISM; CELL-PROLIFERATION; HEME; MECHANISM; INFLAMMATION; DIOXYGENASE; DISCOVERY; BINDING;

D O I：

10.1073/pnas.1719190115

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apoform. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme-heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor-enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.

引用

页码：3249 / 3254

页数：6

共 52 条

[1] Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications [J].