RESUMO
Epacadostat (EPA, INCB024360) is a first-in-class, orally active, investigational drug targeting the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In Phase I studies, EPA has demonstrated promising clinical activity when used in combination with checkpoint modulators. When the metabolism of EPA was investigated in humans, three major, IDO1-inactive, circulating plasma metabolites were detected and characterized: M9, a direct O-glucuronide of EPA; M11, an amidine; and M12, N-dealkylated M11. Glucuronidation of EPA to form M9 is the dominant metabolic pathway, and in vitro, this metabolite is formed by UGT1A9. However, negligible quantities of M11 and M12 were detected when EPA was incubated with a panel of human microsomes from multiple tissues, hepatocytes, recombinant human cytochrome P450s (P450s), and non-P450 enzymatic systems. Given the reductive nature of M11 formation and the inability to define its source, the role of gut microbiota was investigated. Analysis of plasma from mice dosed with EPA following pretreatment with either antibiotic (ciprofloxacin) to inhibit gut bacteria or 1-aminobenzotriazole (ABT) to systemically inhibit P450s demonstrated that gut microbiota is responsible for the formation of M11. Incubations of EPA in human feces confirmed the role of gut bacteria in the formation of M11. Further, incubations of M11 with recombinant P450s showed that M12 is formed via N-dealkylation of M11 by CYP3A4, CYP2C19, and CYP1A2. Thus, in humans three major plasma metabolites of EPA were characterized: two primary metabolites, M9 and M11, formed directly from EPA via UGT1A9 and gut microbiota, respectively, and M12 formed as a secondary metabolite via P450s from M11.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Intestinos/microbiologia , Microbiota , Oximas/metabolismo , Sulfonamidas/metabolismo , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , UDP-Glucuronosiltransferase 1ARESUMO
The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.
Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Janus Quinase 2/antagonistas & inibidores , Mutação de Sentido Incorreto , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores de Trombopoetina/metabolismo , Trombocitose/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Contagem de Plaquetas , Mielofibrose Primária/sangue , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trombocitose/sangue , Trombocitose/genéticaRESUMO
Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.
Assuntos
Células Dendríticas/imunologia , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Antígeno B7-2/imunologia , Antígeno B7-2/metabolismo , Técnicas de Cocultura , Células Dendríticas/enzimologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Linfócitos T/enzimologia , Triptofano Oxigenase/imunologia , Triptofano Oxigenase/metabolismoRESUMO
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.
Assuntos
Pteridinas/química , Pirazinas/química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Ansiolíticos/síntese química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Meia-Vida , Pteridinas/síntese química , Pteridinas/farmacocinética , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-AtividadeRESUMO
The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Diaminas/química , Diaminas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/tratamento farmacológico , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Cristalografia por Raios X , Diaminas/síntese química , Diaminas/farmacocinética , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Modelos Moleculares , Ratos , Relação Estrutura-AtividadeRESUMO
PURPOSE: Bromodomain and extraterminal domain (BET) proteins regulate the expression of many cancer-associated genes and pathways; BET inhibitors have demonstrated activity in diverse models of hematologic and solid tumors. We report the preclinical characterization of INCB054329, a structurally distinct BET inhibitor that has been investigated in phase I clinical trials. EXPERIMENTAL DESIGN: We used multiple myeloma models to investigate vulnerabilities created by INCB054329 treatment that could inform rational combinations. RESULTS: In addition to c-MYC, INCB054329 decreased expression of oncogenes FGFR3 and NSD2/MMSET/WHSC1, which are deregulated in t(4;14)-rearranged cell lines. The profound suppression of FGFR3 sensitized the t(4;14)-positive cell line OPM-2 to combined treatment with a fibroblast growth factor receptor inhibitor in vivo. In addition, we show that BET inhibition across multiple myeloma cell lines resulted in suppressed interleukin (IL)-6 Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling. INCB054329 displaced binding of BRD4 to the promoter of IL6 receptor (IL6R) leading to reduced levels of IL6R and diminished signaling through STAT3. Combination with JAK inhibitors (ruxolitinib or itacitinib) further reduced JAK-STAT signaling and synergized to inhibit myeloma cell growth in vitro and in vivo. This combination potentiated tumor growth inhibition in vivo, even in the MM1.S model of myeloma that is not intrinsically sensitive to JAK inhibition alone. CONCLUSIONS: Preclinical data reveal insights into vulnerabilities created in myeloma cells by BET protein inhibition and potential strategies that can be leveraged in clinical studies to enhance the activity of INCB054329.
Assuntos
Proteínas de Ciclo Celular/genética , Mieloma Múltiplo/tratamento farmacológico , Compostos Orgânicos/farmacologia , Receptores de Interleucina-6/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Animais , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Histona-Lisina N-Metiltransferase/genética , Humanos , Janus Quinases/genética , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Ligação Proteica/efeitos dos fármacos , Proteínas/antagonistas & inibidores , Proteínas/genética , Proteínas Proto-Oncogênicas c-myc/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteínas Repressoras/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidoresRESUMO
A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.
RESUMO
The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Imidazóis/síntese química , Imidazolinas/síntese química , Imidazolinas/química , Imidazolinas/farmacologia , Modelos Moleculares , Relação Estrutura-Atividade , Tiazóis/síntese químicaRESUMO
The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.
Assuntos
Modelos Moleculares , Pteridinas/síntese química , Piridazinas/síntese química , Relação Quantitativa Estrutura-Atividade , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Plexo Corióideo/metabolismo , Lobo Frontal/metabolismo , Técnicas In Vitro , Pteridinas/química , Pteridinas/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , SuínosRESUMO
[structure: see text]. The first asymmetric synthesis of the (S)-1,1-dioxido-isothiazolidin-3-one ((S)-IZD) pTyr mimetic, which has been incorporated into the recently reported potent protein tyrosine phosphatase 1B (PTP1B) inhibitors, is presented herein. The key reaction is the reduction of the (R)-oxido-isothiazolidin-3-one heterocycle with excellent regiochemical and stereochemical control (>98% ee; 82% yield).
Assuntos
Inibidores Enzimáticos/síntese química , Fosfotirosina/química , Tiazóis/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Estereoisomerismo , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Biological targets that are challenging to pursue for medicinal chemists, such as the protein phosphatases, require creative and innovative approaches for identifying and optimizing previously unknown classes of inhibitors. To achieve these lofty objectives, medicinal chemists must utilize the latest computational, structural biology, synthetic and analytical technologies in the drug development process. The iterative use of structure-based drug design often plays a key role, as illustrated by the independent discoveries of two research groups involving the identification and optimization of protein tyrosine phosphatase 1B inhibitors that have novel heterocyclic phosphotyrosine mimetics. The newly designed pharmacophore provides a promising chemical lead for phosphatase drug discovery and a valuable chemical tool for phosphatase research in general.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Animais , Fosfoproteína 32 Regulada por cAMP e Dopamina/antagonistas & inibidores , Inibidores Enzimáticos/química , Humanos , Mimetismo Molecular , Relação Estrutura-AtividadeRESUMO
A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.
RESUMO
Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.
Assuntos
Benzimidazóis/síntese química , Oligopeptídeos/química , Fosfotirosina/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Sulfonamidas/síntese química , Tiazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Humanos , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.
Assuntos
Dipeptídeos/síntese química , Fosfotirosina/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/química , Tiazóis/síntese química , Cristalografia por Raios X , Dipeptídeos/química , Desenho de Fármacos , Modelos Moleculares , Mimetismo Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Relação Quantitativa Estrutura-Atividade , Estereoisomerismo , Tiazóis/químicaRESUMO
[reaction: see text] A novel and efficient synthesis of isothiazolidinone protein tyrosine phosphatase mimetics is presented. A practical, regiospecific microwave-assisted addition of bisulfite to activated olefins, including unprecedented reactions with styrene derivatives, is highlighted.
Assuntos
Alcenos/química , Mimetismo Molecular , Fosfotirosina/química , Sulfitos/química , Tiazóis/química , Micro-Ondas , Estrutura MolecularRESUMO
Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies.
Assuntos
Pirazinas/síntese química , Piridinas/síntese química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Animais , Ansiolíticos/síntese química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva , Cães , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Meia-Vida , Técnicas In Vitro , Masculino , Pirazinas/farmacocinética , Pirazinas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Relação Estrutura-AtividadeRESUMO
The identification of several potent pyrazole-based inhibitors of bacterial dihydroorotate dehydrogenase (DHODase) via a directed parallel synthetic approach is described below. The initial pyrazole-containing lead compounds were optimized for potency against Helicobacter pylori DHODase. Using three successive focused libraries, inhibitors were rapidly identified with the following characteristics: K(i) < 10 nM against H. pylori DHODase, sub-microg/mL H. pylori minimum inhibitory concentration activity, low molecular weight, and >10 000-fold selectivity over human DHODase.
Assuntos
Inibidores Enzimáticos/síntese química , Helicobacter pylori/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Pirazóis/síntese química , Técnicas de Química Combinatória , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Helicobacter pylori/enzimologia , Humanos , Pirazóis/química , Pirazóis/farmacologia , Relação Estrutura-AtividadeRESUMO
[reaction: see text] 2,4,5-Triaryl-imidazoles were synthesized directly from the keto-oxime in moderate to good yields via cyclization to the N-hydroxyimidazole and an unprecedented in situ thermal reduction of the N-O bond upon microwave irradiation at 200 degrees C for 20 min.
RESUMO
[reaction: see text] An efficient synthesis of silanediol-based transition-state inhibitors of proteases is described. A new convergent synthesis has been optimized by using a two-step sequence of hydrosilylation followed by the addition of a silyllithio species to an imine. The method should be applicable to the synthesis of a wide variety of silanediol isosteres to probe the utility of this unique transition-state isostere.
Assuntos
Inibidores de Proteases/síntese química , Silanos/química , Inibidores de Proteases/químicaRESUMO
Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose- and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients.