RESUMO
IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.
RESUMO
A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .
Assuntos
Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HeLa , Humanos , Microssomos Hepáticos/metabolismo , Fenilenodiaminas/síntese química , Fenilenodiaminas/química , Fenilenodiaminas/metabolismo , Relação Estrutura-AtividadeRESUMO
This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.
Assuntos
Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Naftalenossulfonatos/química , Naftalenossulfonatos/farmacologia , Administração Oral , Antagonistas de Receptores de Andrógenos/farmacocinética , Animais , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/farmacocinética , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Naftalenossulfonatos/administração & dosagem , Naftalenossulfonatos/farmacocinética , Ratos , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.
RESUMO
Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.
RESUMO
This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzodiazepinonas/administração & dosagem , Benzodiazepinonas/farmacologia , Receptores Notch/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Benzodiazepinonas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Receptores Notch/metabolismo , Relação Estrutura-AtividadeRESUMO
This article reports the design, synthesis, and evaluation of a novel class of molecules of intermediate size (approximately 7000 Da), which possess both the targeting and effector functions of antibodies. These compoundscalled synthetic antibody mimics targeting prostate cancer (SyAM-Ps)bind simultaneously to prostate-specific membrane antigen and Fc gamma receptor I, thus eliciting highly selective cancer cell phagocytosis. SyAMs have the potential to combine the advantages of both small-molecule and biologic therapies, and may address many drawbacks associated with available treatments for cancer and other diseases.
Assuntos
Anticorpos/metabolismo , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/farmacologia , Desenho de Fármacos , Antígenos de Superfície/química , Antígenos de Superfície/metabolismo , Materiais Biomiméticos/metabolismo , Linhagem Celular Tumoral , Técnicas de Química Sintética , Glutamato Carboxipeptidase II/química , Glutamato Carboxipeptidase II/metabolismo , Humanos , Simulação de Acoplamento Molecular , Peso Molecular , Fagocitose/efeitos dos fármacos , Conformação Proteica , Receptores de IgG/metabolismoRESUMO
A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.
Assuntos
Antineoplásicos/síntese química , Nitrilas/química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Masculino , Nitrilas/síntese química , Nitrilas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/metabolismo , Relação Estrutura-AtividadeRESUMO
Despite an excellent initial response to first-line hormonal treatment, most patients with metastatic prostate cancer will succumb to a hormone-refractory form of the disease. Because these tumors are still dependent on a functional androgen receptor (AR), there is a need to find novel and more potent antiandrogens. While searching for small molecules that bind to the AR and inhibit its transcriptional activity, BMS-641988 was discovered. This novel antiandrogen showed an increased (>1 log) potency compared with the standard antiandrogen, bicalutamide, in both binding affinity to the AR and inhibition of AR-mediated transactivation in cell-based reporter assays. In mature rats, BMS-641988 strongly inhibited androgen-dependent growth of the ventral prostate and seminal vesicles. In the CWR-22-BMSLD1 human prostate cancer xenograft model, BMS-641988 showed increased efficacy over bicalutamide (average percent tumor growth inhibition >90% versus <50%), even at exposure levels of bicalutamide 3-fold greater than what can be attained in humans. Furthermore, BMS-641988 was efficacious in CWR-22-BMSLD1 tumors initially refractory to treatment with bicalutamide. BMS-641988 was highly efficacious in the LuCaP 23.1 human prostate xenograft model, inducing stasis throughout the approximately 30-day dosing. To explore the functional mechanisms of BMS-641988, gene expression profiling analysis was done on CWR-22-BMSLD1 xenograft models in mice. Treatment with BMS-641988 resulted in a global gene expression profile more similar to castration compared with that of bicalutamide. Overall, these data highlight that the unique preclinical profile of BMS-641988 may provide additional understanding for the hormonal treatment of prostate cancer.
Assuntos
Antagonistas de Receptores de Andrógenos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Imidas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Imidas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.
Assuntos
Antagonistas de Receptores de Andrógenos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Isoindóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Administração Oral , Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão , Desenho de Fármacos , Humanos , Isoindóis/síntese química , Isoindóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Nitrilas/farmacologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Ligação Proteica , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Compostos de Tosil/farmacologia , Células Tumorais CultivadasRESUMO
Jasmonate signaling pathway plays an important role in induced plant defense against herbivores and pathogens, including the emission of volatiles that serve as attractants for natural enemies of herbivores. We studied the volatiles emitted from rice plants that were wounded and treated with jasmonic acid (JA) and their effects on the host-searching behavior of the rice brown planthopper, Nilaparvata lugens (Stål), and its mymarid egg parasitoid Anagrus nilaparvatae Pang et Wang. Female adults of N. lugens significantly preferred to settle on JA-treated rice plants immediately after release. The parasitoid A. nilaparvatae showed a similar preference and was more attracted to the volatiles emitted from JA-treated rice plants than to volatiles from control plants. This was also evident from greenhouse and field experiments in which parasitism of N. lugens eggs by A. nilaparvatae on plants that were surrounded by JA-treated plants was more than twofold higher than on control plants. Analyses of volatiles collected from rice plants showed that JA treatment dramatically increased the release of volatiles, which included aliphatic aldehydes and alcohols, monoterpenes, sesquiterpenes, methyl salicylate, n-heptadecane, and several as yet unidentified compounds. These results confirm an involvement of the JA pathway in induced defense in rice plants and demonstrate that the egg parasitoid A. nilaparvatae exploits plant-provided cues to locate hosts. We explain the use of induced plant volatiles by the egg parasitoid by a reliable association between planthopper feeding damage and egg presence.
Assuntos
Ciclopentanos/farmacologia , Hemípteros/parasitologia , Oryza/efeitos dos fármacos , Vespas/fisiologia , Animais , Fatores Quimiotáticos/análise , Fatores Quimiotáticos/metabolismo , Feminino , Odorantes/análise , Oryza/metabolismo , Oryza/parasitologia , Oviposição , Óvulo/parasitologia , Oxilipinas , OlfatoRESUMO
A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.
Assuntos
Antagonistas de Androgênios/síntese química , Indóis/química , Antagonistas de Androgênios/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Indóis/farmacologia , Isoformas de Proteínas , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A novel series of [2.2.1]-azahydantoins has been designed and synthesized in an enantiospecific manner. The ability of these compounds to act as antagonists to the androgen receptor was investigated and several were found to have potent activity in vitro.
Assuntos
Antagonistas de Receptores de Andrógenos , Compostos Aza/síntese química , Compostos Aza/farmacologia , Hidantoínas/síntese química , Hidantoínas/farmacologia , Compostos Aza/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Estudos de Avaliação como Assunto , Humanos , Hidantoínas/química , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.
Assuntos
Antineoplásicos/síntese química , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Oxazóis/síntese química , Tiazóis/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Quinases relacionadas a CDC2 e CDC28/metabolismo , Linhagem Celular Tumoral , Sistema Livre de Células , Cristalografia por Raios X , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Oxazóis/farmacocinética , Oxazóis/farmacologia , Fosforilação , Ratos , Proteína do Retinoblastoma/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Transplante HeterólogoRESUMO
Structure-activity studies of 1H-pyrazolo[3,4-b]pyridine 1 have resulted in the discovery of potent CDK1/CDK2 selective inhibitor 21h, BMS-265246 (CDK1/cycB IC(50)=6 nM, CDK2/cycE IC(50)=9 nM). The 2,6-difluorophenyl substitution was critical for potent inhibitory activity. A solid state structure of 21j, a close di-fluoro analogue, bound to CDK2 shows the inhibitor resides coincident with the ATP purine binding site and forms important H-bonds with Leu83 on the protein backbone.
Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Trifosfato de Adenosina/metabolismo , Sítios de Ligação/efeitos dos fármacos , Quinases relacionadas a CDC2 e CDC28/antagonistas & inibidores , Quinase 2 Dependente de Ciclina , Quinases Ciclina-Dependentes/química , Ligação de Hidrogênio , Indicadores e Reagentes , Leucina/química , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
1H-Pyrazolo[3,4-b]pyridine 3 (SQ-67563) has been shown to be a potent, selective inhibitor of CDK1/CDK2 in vitro. In cells 3 acts as a cytotoxic agent with the ability to block cell cycle progression and/or induce apoptosis. The solid state structure of 3 bound to CDK2 shows 3 resides coincident with the ATP purine binding site and forms important H-bonding interactions with Leu83 on the protein backbone.
Assuntos
Quinases relacionadas a CDC2 e CDC28 , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Bioensaio , Proteína Quinase CDC2/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Quinase 2 Dependente de Ciclina , Feminino , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC(50) values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.