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1.
ACS Med Chem Lett ; 11(7): 1402-1409, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32676146

RESUMO

IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.

2.
ACS Med Chem Lett ; 11(2): 172-178, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32071685

RESUMO

Novel imidazole-based TGFßR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFßR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFß-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFßR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

3.
ACS Med Chem Lett ; 9(11): 1117-1122, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30429955

RESUMO

The multifunctional cytokine TGFß plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFß signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFß receptor kinase inhibitors with excellent selectivity for TGFß receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.

4.
SLAS Discov ; 23(7): 742-750, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29873570

RESUMO

Enhancing antitumor activities of the human immune system is a clinically proven approach with the advent of monoclonal antibodies recognizing programmed cell death protein-1 (PD1) receptors on immune cell surfaces. Historically, using flow cytometry as a means to assess next-generation agent activities was underused, largely due to limits on cell number and assay sensitivity. Here, we leveraged an IntelliCyt high-throughput flow cytometry platform to monitor human dendritic cell maturation and lymphocyte proliferation in mixed lymphocyte reactions. Specifically, we established flow cytometry-based immunophenotyping and screening methodologies capable of measuring T-cell activation as a result of cell-associated antigens presented on dendritic cell surfaces, as indicated by cell proliferation, cytokine secretion, and surface marker expression. Together, the overall novelty of this 384-well platform is its capability to measure multiple functional readouts in one well and consistently evaluate large numbers of compounds in a single study, as well as its ability to show increased assay sensitivity requiring considerably fewer primary cells and less reagents compared to more traditional 96-well flow cytometry methods.


Assuntos
Células Dendríticas/metabolismo , Citometria de Fluxo , Ensaios de Triagem em Larga Escala , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Linfócitos T/metabolismo , Citocinas/metabolismo , Células Dendríticas/imunologia , Citometria de Fluxo/métodos , Humanos , Ativação Linfocitária/imunologia , Linfócitos T/imunologia
5.
J Biomol Screen ; 21(8): 866-74, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27142718

RESUMO

Oral agents targeting Janus-associated kinases (JAKs) are promising new agents in clinical development. To better understand the relationship between JAK inhibition and biological outcome, compounds targeting JAKs were evaluated in peripheral human whole blood. To date, these analyses are low throughput and costly. Here, we developed a robust 384-well, high-throughput flow-based assay approach to screen small molecules for JAK/STAT signaling inhibition in human whole blood. This assay platform provides a highly sensitive analysis of signaling events in blood and facilitates measurement of target engagement. Further, the automation technologies and process optimizations developed here overcame sample integrity, handling, and multiparametric data analysis bottlenecks without affecting assay performance. Together these efforts dramatically increased sample throughput compared to conventional manual flow cytometric approaches and enabled development of novel JAK/STAT inhibitors.


Assuntos
Citometria de Fluxo/métodos , Ensaios de Triagem em Larga Escala/métodos , Inibidores de Proteínas Quinases/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Fosforilação , Inibidores de Proteínas Quinases/química , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Bibliotecas de Moléculas Pequenas/química
6.
ACS Cent Sci ; 2(1): 27-31, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-27163023

RESUMO

The fungal-derived Taiwanese natural product antroquinonol A has attracted both academic and commercial interest due to its reported exciting biological properties. This reduced quinone is currently in phase II trials (USA and Taiwan) for the treatment of non-small-cell lung carcinoma (NSCLC) and was recently granted orphan drug status by the FDA for the treatment of pancreatic cancer and acute myeloid leukemia. Pending successful completion of human clinical trials, antroquinonol is expected to be commercialized under the trade name Hocena. A synthesis-enabled biological re-examination of this promising natural product, however, reveals minimal in vitro and in vivo antitumor activity in preclinical models.

7.
PLoS One ; 9(4): e93441, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24736311

RESUMO

UNLABELLED: ß-arrestins, ubiquitous cellular scaffolding proteins that act as signaling mediators of numerous critical cellular pathways, are attractive therapeutic targets because they promote tumorigenesis in several tumor models. However, targeting scaffolding proteins with traditional small molecule drugs has been challenging. Inhibition of ß-arrestin 2 with a novel aptamer impedes multiple oncogenic signaling pathways simultaneously. Additionally, delivery of the ß-arrestin 2-targeting aptamer into leukemia cells through coupling to a recently described cancer cell-specific delivery aptamer, inhibits multiple ß-arrestin-mediated signaling pathways known to be required for chronic myelogenous leukemia (CML) disease progression, and impairs tumorigenic growth in CML patient samples. The ability to target scaffolding proteins such as ß-arrestin 2 with RNA aptamers may prove beneficial as a therapeutic strategy. HIGHLIGHTS: An RNA aptamer inhibits ß-arrestin 2 activity.Inhibiting ß-arrestin 2 impedes multiple tumorigenic pathways simultaneously.The therapeutic aptamer is delivered to cancer cells using a cell-specific DNA aptamer.Targeting ß-arrestin 2 inhibits tumor progression in CML models and patient samples.


Assuntos
Aptâmeros de Nucleotídeos/genética , Arrestinas/genética , Arrestinas/metabolismo , Leucemia/genética , Leucemia/metabolismo , Transdução de Sinais , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Células K562 , beta-Arrestina 2 , beta-Arrestinas
8.
Mol Cell Biol ; 28(21): 6580-93, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18765637

RESUMO

Overexpression and activation of the steroid receptor coactivator amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) have been shown to have a critical role in oncogenesis and are required for both steroid and growth factor signaling in epithelial tumors. Here, we report a new mechanism for activation of SRC coactivators. We demonstrate regulated tyrosine phosphorylation of AIB1/SRC-3 at a C-terminal tyrosine residue (Y1357) that is phosphorylated after insulin-like growth factor 1, epidermal growth factor, or estrogen treatment of breast cancer cells. Phosphorylated Y1357 is increased in HER2/neu (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) mammary tumor epithelia and is required to modulate AIB1/SRC-3 coactivation of estrogen receptor alpha (ERalpha), progesterone receptor B, NF-kappaB, and AP-1-dependent promoters. c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1/SRC-3 at Y1357 and modulates the association of AIB1 with c-Abl, ERalpha, the transcriptional cofactor p300, and the methyltransferase coactivator-associated arginine methyltransferase 1, CARM1. AIB1/SRC-3-dependent transcription and phenotypic changes, such as cell growth and focus formation, can be reversed by an Abl kinase inhibitor, imatinib. Thus, the phosphorylation state of Y1357 can function as a molecular on/off switch and facilitates the cross talk between hormone, growth factor, and intracellular kinase signaling pathways in cancer.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Histona Acetiltransferases/metabolismo , Fosfotirosina/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transativadores/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Feminino , Proteínas de Fusão bcr-abl , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Coativador 3 de Receptor Nuclear , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Mapeamento de Interação de Proteínas , Fatores de Transcrição/metabolismo
9.
Cancer Res ; 68(10): 3697-706, 2008 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-18483252

RESUMO

Overexpression of the oncogene amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) induces mammary tumorigenesis in mice. In breast cancer, high levels of AIB1/SRC-3 and the growth factor receptor HER2/neu predict resistance to endocrine therapy and poor outcome. However, a mechanistic relationship between AIB1/SRC-3 and HER2/neu in the development of breast cancer has not been shown. Here, we show that deletion of one allele of SRC-3 significantly delays Neu-induced mammary tumor development in mice. Homozygous deletion of SRC-3 in mice completely prevents Neu-induced tumor formation. By ages 3 to 4 months, Neu/SRC-3(+/-) mice exhibit a noticeable reduction in lateral side-bud formation, accompanied by reduced cellular levels of phosphorylated Neu compared with Neu/SRC-3(wt) mice. In Neu-induced tumors, high levels of SRC-3, phosphorylated Neu, cyclin D1, cyclin E, and proliferating cell nuclear antigen expression are observed, accompanied by activation of the AKT and c-Jun NH(2) kinase (JNK) signaling pathways. In comparison, phosphorylated Neu, cyclin D1, and cyclin E are significantly decreased in Neu/SRC-3(+/-) tumors, proliferation is reduced, and AKT and JNK activation is barely detectable. Our data indicate that AIB1/SRC-3 is required for HER2/neu oncogenic activity and for the phosphorylation and activation of the HER2/neu receptor. We predict that reducing AIB1/SRC-3 levels or activity in the mammary epithelium could potentiate therapies aimed at inhibiting HER2/neu signaling in breast cancer.


Assuntos
Histona Acetiltransferases/genética , Histona Acetiltransferases/fisiologia , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Receptor ErbB-2/metabolismo , Transativadores/genética , Transativadores/fisiologia , Alelos , Animais , Proliferação de Células , Epitélio/metabolismo , Deleção de Genes , Histona Acetiltransferases/metabolismo , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Coativador 3 de Receptor Nuclear , Fosforilação , Transdução de Sinais , Transativadores/metabolismo
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