RESUMO
Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of inhibitors with a conformationally constrained bicyclo[3.1.0]hexane core. These potently inhibited IDO1 in a cellular context by binding to the apoenzyme, as elucidated by biochemical characterization and X-ray crystallography. A SKOV3 tumor model was instrumental in differentiating compounds, leading to the identification of IACS-9779 (62) and IACS-70465 (71). IACS-70465 has excellent cellular potency, a robust pharmacodynamic response, and in a human whole blood assay was more potent than linrodostat (BMS-986205). IACS-9779 with a predicted human efficacious once daily dose below 1 mg/kg to sustain >90% inhibition of IDO1 displayed an acceptable safety margin in rodent toxicology and dog cardiovascular studies to support advancement into preclinical safety evaluation for human development.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Tumor-associated macrophages (TAMs) have a significant presence in the tumor stroma across multiple human malignancies and are believed to be beneficial to tumor growth. Targeting CSF1R has been proposed as a potential therapy to reduce TAMs, especially the protumor, immune-suppressive M2 TAMs. Additionally, the high expression of CSF1R on tumor cells has been associated with poor survival in certain cancers, suggesting tumor dependency and therefore a potential therapeutic target. The CSF1-CSF1R signaling pathway modulates the production, differentiation, and function of TAMs; however, the discovery of selective CSF1R inhibitors devoid of type III kinase activity has proven to be challenging. We discovered a potent, highly selective, and orally bioavailable CSF1R inhibitor, IACS-9439 (1). Treatment with 1 led to a dose-dependent reduction in macrophages, promoted macrophage polarization toward the M1 phenotype, and led to tumor growth inhibition in MC38 and PANC02 syngeneic tumor models.
Assuntos
Antineoplásicos/uso terapêutico , Benzotiazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Benzotiazóis/síntese química , Benzotiazóis/farmacocinética , Estabilidade de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Relação Estrutura-Atividade , Células THP-1 , Macrófagos Associados a Tumor/efeitos dos fármacosRESUMO
Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.
RESUMO
Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta[b]benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure-activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation-initiation machinery (i.e., complex 5'-untranslated region UTR) relative to simple 5'UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds 74 and 76 were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol.
Assuntos
Antineoplásicos/síntese química , Inibidores da Síntese de Proteínas/síntese química , Triterpenos/síntese química , Regiões 5' não Traduzidas , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Genes Reporter , Humanos , Luciferases/biossíntese , Luciferases/genética , Camundongos , Microssomos Hepáticos/metabolismo , Inibidores da Síntese de Proteínas/farmacocinética , Inibidores da Síntese de Proteínas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Triterpenos/farmacocinética , Triterpenos/farmacologiaRESUMO
The Hedgehog (Hh) signaling pathway is crucial for normal embryonic development. Aberrant Hh signaling is implicated in numerous pathologic conditions including proliferative diseases such as cancer. During the past decade, academic and industrial research efforts have resulted in the discovery of a variety of Hh pathway antagonists. This review focuses on the most recent advances in this field with particular emphasis on the medicinal chemistry approaches used to discover these Hh antagonists. While most of the small molecule modulators of the Hh pathway were discovered through screening and subsequent medicinal chemistry, a number of them originated from rational design or natural products.
Assuntos
Descoberta de Drogas/métodos , Proteínas Hedgehog/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Neoplasias/tratamento farmacológico , Transdução de SinaisRESUMO
Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.
Assuntos
Descoberta de Drogas , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Transdução de Sinais/efeitos dos fármacos , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular , Humanos , Fígado/citologia , Meduloblastoma/tratamento farmacológico , Meduloblastoma/patologia , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Estereoisomerismo , Alcaloides de Veratrum/química , Alcaloides de Veratrum/farmacocinéticaRESUMO
BACKGROUND: There is increasing evidence suggesting that blocking aberrant Hedgehog (Hh) signaling can be a novel therapeutic avenue for the treatment of cancer. During the past decade, efforts from academic and industrial groups have led to the discovery of a variety of Hh pathway inhibitors. OBJECTIVE: This review covers the patent literature related to Hh pathway inhibitors for the treatment of proliferative diseases, regardless of their modes of action. METHODS: A comprehensive survey of the patent literature since 1999 is presented. RESULTS/CONCLUSION: Most reported Hh pathway inhibitors act on the key signaling transducer Smoothened (SMO). Screening of compound libraries using reporter and binding assays have identified a broad diversity of chemical structures that interact with SMO. These screening approaches, followed by conventional medicinal chemistry, have delivered important clinical drug candidates, such as GDC-0449 and XL-139. In addition, modification of the naturally occurring Veratrum alkaloid cyclopamine has resulted in various active analogues, including clinical drug candidate IPI-926. Although there are recent scientific literature reports of small molecules acting downstream of SMO, there is limited patent literature on this mode of Hh pathway inhibition.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas Hedgehog/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Proteínas Hedgehog/fisiologia , Compostos Heterocíclicos/farmacologia , Humanos , Patentes como Assunto , Interferência de RNARESUMO
Laulimalide is a cytotoxic natural product isolated from marine sponges. It is structurally distinct from taxanes. However, like paclitaxel, laulimalide binds to tubulin and enhances microtubule assembly and stabilization. It exhibits potent inhibition of cellular proliferation with IC50 values in the low nM range against numerous cancer cell lines. In contrast to paclitaxel, however, laulimalide is also very potent against multidrug-resistant (MDR) cancer cell lines which overexpress P-glycoprotein (PgP). It has unique structural and biological properties, and attempts at synthesis have attracted considerable effort in recent years, resulting in more than ten published total syntheses. Despite this extensive attention, there have been no reported in vivo evaluations of laulimalide to date, probably due to the structural complexity of laulimalide and the scarcity of natural material. In our studies to explore the therapeutic potential of laulimalide, a total synthesis capable of producing gram quantities of laulimalide was designed, which enabled both in vitro and in vivo evaluation. Our in vitro results with synthetic material confirmed the previous reports that laulimalide is a mitotic blocker that can inhibit the growth of a variety of both non-MDR and MDR human cancer cell lines. However, despite demonstrating promise in cell-based and pharmacokinetic studies, laulimalide exhibited only minimal tumor growth inhibition in vivo and was accompanied by severe toxicity and mortality. The unfavorable efficacy to toxicity ratio in vivo suggests that laulimalide may have limited value for development as a new anticancer therapeutic agent.
Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Microtúbulos/efeitos dos fármacos , Taxoides/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Macrolídeos , Biologia Marinha , Camundongos , Taxoides/farmacocinética , Taxoides/toxicidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The steroidogenic enzyme type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the synthesis of estradiol (E(2)), a hormone well-known to stimulate the growth of estrogen-sensitive tumors. To obtain compounds able to control E(2) formation, two moieties were linked with a methylene side chain: an adenosine moiety for interacting with the cofactor-binding site and an E(2) moiety for interacting with the substrate-binding site. When tested as inhibitors of type 1 17beta-HSD, the hybrid compounds inhibited the reductive activity (E(1) into E(2)) with IC(50) values ranging from 52 to 1,000 nM. The optimal side-chain length was determined to be eight methylene groups for a 16 beta-orientation. The presence of two components (E(2) and adenosine) is essential for good inhibition, since 16 beta-nonyl-E(2) and 5-nonanoyl-O-adenosine, two compounds having only one of the components, did not inhibit the enzyme. Moreover, the 3D-structure analysis of EM-1,745 complexed with type 1 17beta-HSD showed key interactions with both substrate- and cofactor-binding sites.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Adenosina/análogos & derivados , Inibidores Enzimáticos/síntese química , Estradiol/análogos & derivados , Adenosina/síntese química , Adenosina/farmacologia , Linhagem Celular , Inibidores Enzimáticos/farmacologia , Estradiol/síntese química , Estradiol/farmacologia , Humanos , Ligação de Hidrogênio , Rim/embriologia , Rim/enzimologia , Modelos MolecularesRESUMO
Breast cancer is the second most frequent cancer affecting women. Among all endocrine therapies for the treatment of breast cancer, inhibition of estrogen biosynthesis is becoming an interesting complementary approach to the use of antiestrogens. The enzyme type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD) plays a critical role in the biosynthesis of estradiol catalyzing preferentially the reduction of estrone into estradiol, the most active estrogen. Consequently, this enzyme is an interesting biological target for designing drugs for the treatment of estrogen-sensitive diseases such as breast cancer. Our group has reported the synthesis and the biological evaluation of N-methyl, N-butyl 6beta-(thiaheptamamide)estradiol as a potent reversible inhibitor of type 1 17beta-HSD. Unfortunately, this inhibitor has shown an estrogen effect, thus reducing its possible therapeutic interest. Herein three strategies to modify the biological profile (estrogenicity and inhibitory potency) of the initial lead compound were reported. In a first approach, the thioether bond was replaced with a more stable ether bond. Secondly, the hydroxyl group at position 3, which is responsible for a tight binding with the estrogen receptor, was removed. Finally, the amide group of the side-chain was changed to a methyl group. Moreover, the relationship between the inhibitory potency and the configuration of the side-chain at position 6 was investigated. The present study confirmed that the 6beta-configuration of the side chain led to a much better inhibition than the 6alpha-configuration. The replacement of the 3-OH by a hydrogen atom as well as that of the amide group by a methyl was clearly unfavorable for the inhibition of type 1 17beta-HSD. Changing the thioether for an ether bond decreased by 10-fold the estrogenic profile of the lead compound while the inhibitory potency on type 1 17beta-HSD was only decreased by 5-fold. This study contributes to the knowledge required for the development of compounds with the desired profile, that is, a potent inhibitor of type 1 17beta-HSD without estrogen-like effects.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Estradiol/metabolismo , Estrogênios/metabolismo , Neoplasias da Mama/metabolismo , Catálise , Cromatografia Líquida de Alta Pressão , DNA/química , Estradiol/química , Éteres , Feminino , Humanos , Hidrogênio/química , Espectroscopia de Ressonância Magnética , Modelos Químicos , Receptores de Estrogênio/metabolismo , Esteroides/metabolismoRESUMO
Analogues of the marine natural product (-)-laulimalide were prepared by total synthesis and evaluated in vitro for anticancer activity.
Assuntos
Antineoplásicos/síntese química , Neoplasias da Mama/patologia , Neoplasias do Colo/patologia , Taxoides/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Divisão Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Feminino , Humanos , Macrolídeos , Estrutura Molecular , Relação Estrutura-Atividade , Taxoides/química , Células Tumorais CultivadasRESUMO
Human estrogenic 17beta-hydroxysteroid dehydrogenase (17beta-HSD type 1) catalyzes the final step in the synthesis of active estrogens that stimulate the proliferation of breast cancer cells. Based on the initial premise to make use of the binding energies of both the substrate and cofactor sites, and molecular modeling starting from the enzyme structure, several estradiol-adenosine hybrids were designed and synthesized. Among these hybrids, EM-1745 with a linker of 8-CH2 groups is proved to be the best competitive inhibitor with a Ki of 3.0 +/- 0.8 nM. The crystal structure of the EM-1745 enzyme complex at 1.6 A provides evidence at atomic resolution of strong interactions between both the steroid and cofactor moieties and the enzyme molecule, as illustrated by a deltaA-weighted 2Fo-Fc electron density map contoured at 3.0 delta. The substrate entry loop is further stabilized in this complex compared with previous complexes of the enzyme. These results confirm our initial strategy of combining studies of structural biology and enzyme mechanism in the inhibitor design, which may be applied to other steroidogenic enzymes involved in human diseases.