This Perspective illustrates the defining characteristics of free radical chemistry, beginning with its rich and storied history. Studies from our laboratory are discussed along with recent developments emanating from others in this burgeoning area. The practicality and chemoselectivity of radical reactions enable rapid access to molecules of relevance to drug discovery, agrochemistry, material science, and other disciplines. Thus, these reactive intermediates possess inherent translational potential, as they can be widely used to expedite scientific endeavors for the betterment of humankind.

Radicals: Reactive Intermediates with Translational Potential

Since the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) as an attractive target for anticancer therapy in 2003, the search for inhibitors has been intensely pursued both in academia and in pharmaceutical companies. Many novel IDO1 inhibitor scaffolds have been described, and a few potent compounds have entered clinical trials. However, a significant number of the reported compounds contain problematic functional groups, suggesting that enzyme inhibition could be the result of undesirable side reactions instead of selective binding to IDO1. Here, we describe issues in the employed experimental protocols, review and classify reported IDO1 inhibitors, and suggest different approaches for confirming viable inhibitor scaffolds.

https://pubsdc3.acs.org/doi/pdfplus/10.1021/acs.jmedchem.5b00326

Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

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 apo-form. 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.

https://www.pnas.org/content/pnas/115/13/3249.full.pdf

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

A new approach for the synthesis of 1,4-dicarbonyl compounds is reported. Chemoselective activation of amide carbonyl functionality and subsequent umpolung via N-oxide addition generates an electrophilic enolonium species that can be coupled with a wide range of nucleophilic enolates. The method conveys broad functional group tolerance on both components, does not suffer from formation of homocoupling byproducts and avoids the use of transition metal catalysts.

Chemoselective Intermolecular Cross-Enolate-Type Coupling of Amides

Irreversible inhibitors of G12C mutant K-Ras protein are provided. Also disclosed are methods to modulate the activity of G12C mutant K-Ras protein and methods of treatment of disorders mediated by G12C mutant K-Ras protein.

Covalent inhibitors of kras g12c

There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention.

Inhibitors of indoleamine 2,3-dioxygenase (ido)

The invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. The Formula (I) imidazotriazines inhibit protein kinase activity thereby making them useful as anticancer agents.

Imidazotriazinecarbonitriles useful as kinase inhibitors

The invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I imidazopyridazines inhibit protein kinase activity thereby making them useful as anticancer agents.

Substituted imidazopyridazines useful as kinase inhibitors

The invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof. The Formula (I) imidazopyridazines inhibit protein kinase activity thereby making them useful as anticancer agents.

Imidazopyridazinecarbonitriles useful as kinase inhibitors

Disclosed are compounds of Formula (I): (Formula (I)) wherein: R 1 is -CH 2 CH 2 CF 3 ; R 2 is -CH 2 CH 2 CH 2 F, -CH 2 CF 2 CH 3 , -CH 2 CH 2 CF 3 , -CH 2 CH(CH 3 )CF 3 , -CH 2 CH 2 CF 2 CH 3 , (Formulae (II), (III), (IV), (V) or (VI): R 3 is H or -CH 3 ; Ring A is phenyl or pyridinyl; and R x , R y , R a , R b , y, and z are defined herein. Also disclosed are methods of using such compounds to inhibit the Notch receptor, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as cancer.

Fluoroalkyl and fluorocycloalkyl 1,4-benzodiazepinone compounds as notch|inhibitors

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