RESUMO
Mutant BRAFV600E is one of the most common oncogenic drivers in metastatic melanoma. While first generation BRAFV600E inhibitors are capable of controlling tumors systemically, they are unable to adequately treat tumors that have metastasized to the brain due to insufficient penetration across the blood-brain barrier (BBB). Through a combination of structure-based drug design (SBDD) and the optimization of physiochemical properties to enhance BBB penetration, we herein report the discovery of the brain-penetrant BRAFV600E inhibitor PF-07284890 (ARRY-461). In mice studies, ARRY-461 proved to be highly brain-penetrant and was able to drive regressions of A375 BRAFV600E tumors implanted both subcutaneously and intracranially. Based on compelling preclinical safety and efficacy studies, ARRY-461 was progressed into a Phase 1 A/B clinical trial (NCT04543188).
Assuntos
Antineoplásicos , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Humanos , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Feminino , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Melanoma/tratamento farmacológico , Melanoma/patologia , Relação Estrutura-Atividade , Ratos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , MasculinoRESUMO
Chromodomain helicase DNA-binding protein 1 like (CHD1L) is an oncogene implicated in tumor progression, multidrug resistance, and metastasis in many types of cancer. In this article, we described the optimization of the first lead CHD1L inhibitors (CHD1Li) through drug design and medicinal chemistry. More than 30 CHD1Li were synthesized and evaluated using a variety of colorectal cancer (CRC) tumor organoid models and functional assays. The results led to the prioritization of six lead CHD1Li analogues with improved potency, antitumor activity, and drug-like properties including metabolic stability and in vivo pharmacokinetics. Furthermore, lead CHD1Li 6.11 proved to be an orally bioavailable antitumor agent, significantly reducing the tumor volume of CRC xenografts generated from isolated quasi mesenchymal cells (M-phenotype), which possess enhanced tumorigenic properties. In conclusion, we reported the optimization of first-in-class inhibitors of oncogenic CHD1L as a novel therapeutic strategy with potential for the treatment of cancer.
Assuntos
Antineoplásicos , DNA Helicases , Proteínas de Ligação a DNA , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/genética , Linhagem Celular Tumoral , DNA Helicases/antagonistas & inibidores , Proteínas de Ligação a DNA/antagonistas & inibidores , Desenho de Fármacos , Humanos , OncogenesRESUMO
Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin's blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes.
Assuntos
Gluconeogênese/efeitos dos fármacos , Glicerolfosfato Desidrogenase/antagonistas & inibidores , Metformina/farmacologia , Mitocôndrias/enzimologia , Animais , Glicemia/análise , Glicemia/biossíntese , Células Cultivadas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/metabolismo , Glicerolfosfato Desidrogenase/deficiência , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ácido Láctico/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Knockout , Oxirredução/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels-Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC50s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.
Assuntos
Processamento Alternativo , Antineoplásicos/síntese química , Desenho de Fármacos , Compostos de Epóxi/síntese química , Álcoois Graxos/síntese química , Macrolídeos/síntese química , Piranos/síntese química , Precursores de RNA/genética , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Humanos , Concentração Inibidora 50 , Macrolídeos/química , Macrolídeos/farmacologia , Modelos Moleculares , Estrutura Molecular , Proteínas Proto-Oncogênicas c-mdm2/genética , Piranos/química , Piranos/farmacologiaRESUMO
From random screening of our compound libraries, we identified a hit compound with an IC50 of 27 microM against hepatitis C viral NS5B RNA-dependent RNA polymerase. By using a parallel synthetic strategy, a series of its derivatives were synthesized. From their anti-HCV activity screening, compounds with single digital 3.8 micromolar activity were obtained.
Assuntos
Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Indóis/síntese química , Indóis/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Uracila/análogos & derivados , Antivirais/síntese química , Antivirais/farmacologia , Inibidores Enzimáticos/síntese química , Hepacivirus/enzimologia , Humanos , Concentração Inibidora 50 , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-Atividade , Uracila/síntese química , Uracila/farmacologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
From compound library screening using an HCV NS5B RNA-dependent RNA polymerase enzymatic assay, we identified a pteridine hit compound with an IC(50) of 15 microM. Our SAR studies were focused on the different groups at the 6- and 7-positions, substitutions at the 4-position, and replacement of N(1) or N(3) with carbon in the pteridine ring. We found that NH or OH at 4-position is critical for the inhibitory activity. Furthermore, a hydrophobic substituent at the 4-position may help compounds permeate through the cell membrane.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Pteridinas/síntese química , Pteridinas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Antivirais/farmacologia , Humanos , Concentração Inibidora 50 , Replicon/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
Ten new beta-D-ribofuranosyl and 2'-beta-C-methyl-beta-D-ribofuranosyl triciribine derivatives 4-13 with various N4 and 6-N substituents on the tricyclic ring were synthesized from the corresponding toyocamycin and new 2'-beta-C-methyl toyocamycin derivatives. The inhibitory studies of these compounds in the HCV replicon assay reveal that some of them possess interesting anti-HCV properties with low cytotoxicity.