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1.
Sci Rep ; 7(1): 13853, 2017 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-29062039

RESUMO

Mutations in IDH1 are highly prevalent in human glioma. First line treatment is radiotherapy, which many patients often forego to avoid treatment-associated morbidities. The high prevalence of IDH1 mutations in glioma highlights the need for brain-penetrant IDH1 mutant-selective inhibitors as an alternative therapeutic option. Here, we have explored the utility of such an inhibitor in IDH1 mutant patient-derived models to assess the potential therapeutic benefits associated with intracranial 2-HG inhibition. Treatment of mutant IDH1 cell line models led to a decrease in intracellular 2-HG levels both in vitro and in vivo. Interestingly, inhibition of 2-HG production had no effect on in vitro IDH1 mutant glioma cell proliferation. In contrast, IDH1 mutant-selective inhibitors provided considerable survival benefit in vivo. However, even with near complete inhibition of intratumoral 2-HG production, not all mutant glioma models responded to treatment. The results suggest that disruption of 2-HG production with brain-penetrant inhibitors in IDH1 mutant gliomas may have substantial patient benefit.


Assuntos
Neoplasias Encefálicas/mortalidade , Inibidores Enzimáticos/farmacologia , Glioma/mortalidade , Glutaratos/metabolismo , Isocitrato Desidrogenase/antagonistas & inibidores , Proteínas Mutantes/antagonistas & inibidores , Mutação , Adulto , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Feminino , Perfilação da Expressão Gênica , Glioma/tratamento farmacológico , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Camundongos Endogâmicos C57BL , Camundongos SCID , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Res ; 77(1): 112-122, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27784746

RESUMO

Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of CRLX101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. CRLX101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. CRLX101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of CRLX101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, CRLX101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with CRLX101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for CRLX101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for CRLX101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR.


Assuntos
Camptotecina/farmacologia , Ciclodextrinas/farmacologia , Reparo do DNA/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Radiossensibilizantes/farmacologia , Neoplasias Retais/patologia , Animais , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiorradioterapia/métodos , Imunofluorescência , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Nanoconjugados , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Res ; 76(15): 4493-503, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27325647

RESUMO

VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. ©2016 AACR.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Camptotecina/uso terapêutico , Ciclodextrinas/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Bevacizumab/administração & dosagem , Bevacizumab/farmacologia , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Linhagem Celular Tumoral , Ciclodextrinas/administração & dosagem , Ciclodextrinas/farmacologia , Feminino , Humanos , Camundongos , Camundongos SCID , Nanopartículas , Neoplasias de Mama Triplo Negativas/patologia
4.
Mol Cancer Ther ; 15(4): 548-59, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26832798

RESUMO

The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single-nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V(600E)) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable antitumor responses in BRAF(V600) (E)-mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK, and concurrent BRAF/MEK inhibitor-resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and, in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long-term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G(186D)) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif. Mol Cancer Ther; 15(4); 548-59. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Ratos
5.
ACS Med Chem Lett ; 7(1): 40-5, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819663

RESUMO

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.

6.
Cancer Discov ; 3(7): 742-50, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23614898

RESUMO

The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinase Quinase Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Mutação , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
7.
Biochem J ; 436(2): 331-9, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21410432

RESUMO

CARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1.


Assuntos
Indóis/antagonistas & inibidores , Indóis/química , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/química , Pirazóis/antagonistas & inibidores , Pirazóis/química , Sequência de Aminoácidos , Domínio Catalítico/efeitos dos fármacos , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Indóis/metabolismo , Dados de Sequência Molecular , Ligação Proteica/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/metabolismo , Pirazóis/metabolismo
8.
Anal Biochem ; 402(1): 65-8, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20338149

RESUMO

Histone acetyl transferases are important regulators of cellular homeostasis. This study describes a sensitive acetyl transferase electrophoretic mobility shift assay applicable both for kinetic analysis of acetyl transferase inhibitors and for high-throughput testing. Application of the assay for human GCN5L2 enabled dissection of inhibitor competition with respect to acetyl coenzyme A. Furthermore, we demonstrated that the assay can detect time-dependent inhibition of human GCN5L2 by reactive inhibitors.


Assuntos
Ensaio de Desvio de Mobilidade Eletroforética/métodos , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Acetilcoenzima A/metabolismo , Animais , Linhagem Celular , Humanos , Cinética
11.
Bioorg Med Chem Lett ; 18(15): 4438-41, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18619839

RESUMO

This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound 7b is a potent, selective inhibitor of CARM1.


Assuntos
Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Técnicas de Química Combinatória , Estrutura Molecular , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade
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