Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme enzyme that catalyzes the oxidation of L-tryptophan. Functionally, IDO1 has played a pivotal role in cancer immune escape via catalyzing the initial step of the kynurenine pathway, and overexpression of IDO1 is also associated with poor prognosis in various cancers. Currently, several small-molecule candidates and peptide vaccines are currently being assessed in clinical trials. Furthermore, the “proteolysis targeting chimera” (PROTAC) technology has also been successfully used in the development of IDO1 degraders, providing novel therapeutics for cancers. Herein, we review the biological functions of IDO1, structural biology and also extensively summarize medicinal chemistry strategies for the development of IDO1 inhibitors in clinical trials. The emerging PROTAC-based IDO1 degraders are also highlighted. This review may provide a comprehensive and updated overview on IDO1 inhibitors and their therapeutic potentials.

/pdf/indoleamine-2-3-dioxygenase-1-ido1-inhibitors-in-clinical-1hk8fghl5x.pdf

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy

Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges.

Abstract Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target protein and E3 ubiquitin ligase together to trigger proteasomal degradation of target protein by the ubiquitin-proteasome system. PROTAC has emerged as a promising approach for targeted therapy in various diseases, particularly in cancers. In this review, we introduce the principle and development of PROTAC technology, as well as the advantages of PROTACs over traditional anti-cancer therapies. Moreover, we summarize the application of PROTACs in targeting critical oncoproteins, provide the guidelines for the molecular design of PROTACs and discuss the challenges in the targeted degradation by PROTACs. 

/pdf/proteolysis-targeting-chimeras-protacs-in-cancer-therapy-3qtnp7bw.pdf

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Developments of CRBN-based PROTACs as potential therapeutic agents

https://molecular-cancer.biomedcentral.com/track/pdf/10.1186/s12943-021-01434-3

Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1.

The design of three novel fatty nitrogen mustard-based anticancer agents with fluorophores incorporated into the alkene structure (CXL 118, CXL121, and CXL122) is described in this report. The results indicated that these compounds are selectively located in lysosomes and exhibit effective antitumour activity. Notably, these compounds can directly serve as both reporting and imaging agents in vitro and in vivo without the need to add other fluorescent tagging agents.

Novel lysosome-targeted anticancer fluorescent agents used in zebrafish and nude mouse tumour imaging

TGF-β signaling plays an extremely important role in the occurrence and development of type 2 diabetes mellitus (T2DM), and the blockade of TGF-β/Smad3 pathway protests against the high-fat diet-induced obesity and diabetes. As a specific small molecule inhibitor of Smad3 protein, the biological activities of compound SIS3 were evaluated by high-fat diet-induced T2DM model mice. In vivo results indicated that SIS3 can not only significantly reduce the body weight, fat mass, and fasting blood glucose in high-fat diet-induced T2DM model mice, but also improve insulin sensitivity and oral glucose tolerance of high-fat diet-induced T2DM model mice after the injection of SIS3 with 5 mg/kg for 45 days.

SIS3, a good candidate for the reverse of type 2 diabetes mellitus in mice

Nonalcoholic fatty liver disease (NAFLD) is featured with liver fat infiltration and accumulation with no connection with overdrinking. With the rising trends and no FDA-approved drugs, NAFLD attracts global attention. In this study, we successfully synthesized 18 novel SIS3 derivatives and evaluated them for pharmacological activity. F-9 and F-15 had potent weight-losing effects. Importantly, intraperitoneal administration of F-9 at 10 mg·kg−1·day−1 for 5 weeks had the most excellent effects to reduce the weight of the body, liver, and fat, as well as adjusting serum levels of AST, ALT, TC, TG, HDL, and LDL. H&E staining showed that F-9 could suppress fat deposition and increase the adipocyte size in the liver.

https://downloads.hindawi.com/journals/jchem/2022/2386212.pdf

Bin Chen

Papers

Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1.

Novel lysosome-targeted anticancer fluorescent agents used in zebrafish and nude mouse tumour imaging

SIS3, a good candidate for the reverse of type 2 diabetes mellitus in mice

Design, Synthesis, and Biological Evaluation of Novel Pyrrolo [2,3-b] Pyridine Derivatives for Nonalcoholic Fatty Liver Disease