SignificanceIndoleamine 2,3-dioxygenase (IDO1) is a heme protein that catalyzes the dioxygenation of tryptophan. Cells expressing this activity are able to profoundly alter their surrounding environment to suppress the immune response. Cancer cells exploit this pathway to avoid immune-mediated destruction. Through a range of kinetic, structural, and cellular assays, we show that two classes of highly selective inhibitors of IDO1 act by competing with heme binding to apo-IDO1. This shows that IDO1 is dynamically bound to its heme cofactor in what is likely a critical step in the regulation of this enzyme. These results have elucidated a previously undiscovered role for the ubiquitous heme cofactor in immune regulation, and it suggests that other heme proteins in biology may be similarly regulated.

SPRYCEL (dasatinib; Bristol-Myers Squibb, Princeton, NJ) is a multiple kinase inhibitor that potently inhibits Bcr-Abl, Src family (Src, Lck, Yes, Fyn), c-Kit, EPHA2, and platelet-derived growth factor receptor ␤ kinases (Lombardo et al., 2004;Shah et al., 2004;Das et al., 2006). It is currently approved in the United States and European Union to treat chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec, Novartis, Basel, Switzerland). Unlike imatinib mesylate, which binds to the closed confirmation of Bcr-Abl kinase, dasatinib was designed to bind to both the open and closed form of the enzyme (Shah et al., 2004;Tokarski et al., 2006). Because of this binding property and the ability to inhibit multiple kinases, including Src, dasatinib is effective in tumors that are resistant to imatinib mesylate (O'Hare et al., 2005;Schittenhelm et al., 2006). Clinical studies have shown that dasatinib shows clinical response in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib mesylate treatment Hochhaus et al., 2006;Talpaz et al., 2006;Quintas-Cardama et al., 2007).Numerous in vitro and in vivo studies have been conducted with dasatinib in nonclinical species to understand its absorption, distribution, metabolism, and excretion (ADME) properties and gauge the suitability of these species as toxicological models Kamath et al., 2008). The metabolic profiles from in vitro studies in liver microsomes, and hepatocytes showed good correlation with the in vivo profiles generated after a single p.o. dose of [14 C]dasatinib to rats and monkeys. The primary metabolites of dasatinib Article, publication date, and citation information can be found at

Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

A two-step degradation-reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickelmediated decarboxylative carboxylation to afford a range of complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality and operational simplicity of the protocol was demonstrated by its use in an industrial carbon-14 radiolabeling setting.

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