Development of Indoleamine 2,3-Dioxygenase 1 Inhibitors for Cancer Therapy and Beyond: A Recent Perspective

Feng, Xi; Dong-dong, Liao; Liu, Dongyu; An, Ping; Li, Zhiyu; Bian, Jinlei

doi:10.1021/acs.jmedchem.0c00925

Cited by 44 publications

(37 citation statements)

References 167 publications

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“…Over the past two decades, researchers have paid close attention to IDO1 as a drug target involved in the molecular mechanisms of tumor immune escape [ 14 , 15 , 16 ]. This has fostered the design of catalytic inhibitors of IDO1 ( 7 – 14 ; Figure 2 ) for the development of immunotherapeutic drugs that make tumor cells more vulnerable to T cell detection and destruction [ 17 , 18 ]. Despite the large amount of research devoted to the design and synthesis of such compounds [ 19 ], few IDO1 inhibitors have entered clinical trials ( 7 – 9 , 12 , 13 ) and recent disappointing results bolster the quest for novel IDO1 inhibitors with more efficacious pharmacological and clinical profiles [ 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls

Mammoli

Bianconi

Ruta

et al. 2022

IJMS

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Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns.

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Section: Introductionmentioning

confidence: 99%

Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls

Mammoli

Bianconi

Ruta

et al. 2022

IJMS

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“…Compound 44, in which the [1,2,4] triazolo [4,3-a]pyridine is substituted with a naphthalene group is devoid of activity, suggesting a lack of interaction of this compound with the heme group. Interestingly, the indazole group can potentially drive the iron-binding, [21,[38][39][40] but the lack of activity of compound 44 suggests that the preferential pose for VS9 analogues does not favour the interaction of this moiety with pocket A. This hypothesis is also supported by the MD simulation in which the indazole moiety of VS9 is stabilized in pocket B for the entire duration of the simulation (Figure 2).…”

Section: Resultsmentioning

confidence: 80%

The [1,2,4]Triazolo[4,3‐a]pyridine as a New Player in the Field of IDO1 Catalytic Holo‐Inhibitors

et al. 2021

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Inhibitors of indoleamine 2,3‐dioxygenase 1 (IDO1) are considered a promising strategy in cancer immunotherapy as they are able to boost the immune response and to work in synergy with other immunotherapeutic agents. Despite the fact that no IDO1 inhibitor has been approved so far, recent studies have shed light on the additional roles that IDO1 mediates beyond its catalytic activity, conferring new life to the field. Here we present a novel class of compounds originated from a structure‐based virtual screening made on IDO1 active site. The starting hit compound is a novel chemotype based on a [1,2,4]triazolo[4,3‐a]pyridine scaffold, so far underexploited among the heme binding moieties. Thanks to the rational and in silico‐guided design of analogues, an improvement of the potency to sub‐micromolar levels has been achieved, with excellent in vitro metabolic stability and exquisite selectivity with respect to other heme‐containing enzymes.

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“…So manual test is feasible, but for a limited number of samples. We took ten articles [34][35][36][37][38][39][40][41][42][43] to test our method on the real data. Structures that represent reaction mechanisms were excluded, so we regarded only molecules and Markush templates.…”

Section: Validation On Real Datamentioning

confidence: 99%

Image2SMILES: Transformer‐Based Molecular Optical Recognition Engine**

et al. 2022

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The rise of deep learning in various scientific and technology areas promotes the development of AI-based tools for information retrieval. Optical recognition of organic structures is a key part of the automated extraction of chemical information. However, this is a challenging task because there is a large variety of representation styles. In this research, we present a Transformer-based artificial neural network to convert images of organic structures to molecular structures. To train the model, we created a comprehensive data generator that stochastically simulates various drawing styles, functional groups, functional group placeholders (R-groups), and visual contamination. We demonstrate that the Transformer-based architecture can gather chemical insights from our generator with almost absolute confidence. That means that, with Transformer, one can fully concentrate on data simulation to build a good recognition model. A web demo of our optical recognition engine is available online at Syntelly platform, and the code for dataset generation is available on GitHub.

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Development of Indoleamine 2,3-Dioxygenase 1 Inhibitors for Cancer Therapy and Beyond: A Recent Perspective

Cited by 44 publications

References 167 publications

Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls

Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls

The [1,2,4]Triazolo[4,3‐a]pyridine as a New Player in the Field of IDO1 Catalytic Holo‐Inhibitors

Image2SMILES: Transformer‐Based Molecular Optical Recognition Engine**

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