RESUMO
As a population, non-Hodgkin's lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2(High)) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2(High) cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-XL-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2(High) NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2(Low) NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-XL inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2(Low)) that could benefit from BCL-XL (navitoclax)-driven combination therapy.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Proteína bcl-X/antagonistas & inibidores , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Indóis/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidoresRESUMO
The anti-apoptotic protein MCL-1 is a key regulator of cancer cell survival and a known resistance factor for small-molecule BCL-2 family inhibitors such as ABT-263 (navitoclax), making it an attractive therapeutic target. However, directly inhibiting this target requires the disruption of high-affinity protein-protein interactions, and therefore designing small molecules potent enough to inhibit MCL-1 in cells has proven extremely challenging. Here, we describe a series of indole-2-carboxylic acids, exemplified by the compound A-1210477, that bind to MCL-1 selectively and with sufficient affinity to disrupt MCL-1-BIM complexes in living cells. A-1210477 induces the hallmarks of intrinsic apoptosis and demonstrates single agent killing of multiple myeloma and non-small cell lung cancer cell lines demonstrated to be MCL-1 dependent by BH3 profiling or siRNA rescue experiments. As predicted, A-1210477 synergizes with the BCL-2/BCL-XL inhibitor navitoclax to kill a variety of cancer cell lines. This work represents the first description of small-molecule MCL-1 inhibitors with sufficient potency to induce clear on-target cellular activity. It also demonstrates the utility of these molecules as chemical tools for dissecting the basic biology of MCL-1 and the promise of small-molecule MCL-1 inhibitors as potential therapeutics for the treatment of cancer.
Assuntos
Compostos de Anilina/farmacologia , Apoptose/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Neoplasias/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Ácidos Carboxílicos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Indóis/farmacologia , Proteínas de Membrana/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas/metabolismoAssuntos
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Type 2 diabetes is a widespread disease where effective pharmacologic therapies can have a profound beneficial public health impact. Increased hepatic glucose production (HGP) is observed in diabetics and its moderation by currently available agents provides therapeutic benefits. This review describes the challenges associated with the discovery of small molecules that inhibit HGP. Gluconeogenesis, glycogenolysis, liver architecture, and hepatocyte composition are described to provide background information on hepatic function. Current methods of target validation for drug discovery, HGP measurement, diabetes animal models, as well as current drug therapies are covered. In the accompanying review article the new drug targets being probed to produce the next generation of therapies are described. Significant pharmaceutical and academic efforts to pharmacologically inhibit HGP has the opportunity to provide new therapeutics for type 2 diabetics.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/biossíntese , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Animais , Proteínas de Transporte/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Circulação Êntero-Hepática/efeitos dos fármacos , Humanos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Fatores de Transcrição/agonistas , Fatores de Transcrição/antagonistas & inibidoresRESUMO
A number of therapeutic targets are currently under investigation for inhibition of hepatic glucose production with small molecules. Antagonists of the glucagon receptor, glycogen phosphorylase, 11-beta-hydroxysteroid dehydrogenase-1 and fructose 1,6-bisphosphatase are, or have been, under evaluation in human clinical trials. Other strategies, including glucocorticoid receptor antagonists and carnitine palmitoyltransferase inhibitors, are supported by proof of principle studies in man as well as rodents. Several potential targets including glucose-6-phosphatase, glucose-6-phosphatase translocase, glycogen synthase kinase-3, adenosine receptor 2B antagonists, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase kinase, have been validated by compounds that are effective in animal models. Other targets like PGC-1a and CREB have initial validation support but no medicinal chemistry has been reported.
Assuntos
Glucose/biossíntese , Fígado/efeitos dos fármacos , Fígado/metabolismo , Animais , Depressão Química , HumanosRESUMO
Constrained analogues 5-7 of the potent and subtype selective somatostatin mimetic 1 were prepared by incorporating conformational constraints into the nine-membered heterocyclic scaffold. Each constrained peptidomimetic showed an altered activity profile relative to lead compound 1, with compound 7 exhibiting a 25-fold and 2-fold binding enhancement against somatostatin receptor subtypes sst4 and sst5, respectively.
Assuntos
Mimetismo Molecular , Somatostatina/análogos & derivados , Ligação Competitiva , Humanos , Concentração Inibidora 50 , Ligantes , Receptores de Somatostatina/antagonistas & inibidores , Somatostatina/síntese química , Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
A library of 951 compounds based upon the beta-turn motif were examined for their ability to stimulate the melanocortin-1 receptor. From this screening process, we have identified two compounds possessing low micromolar agonist activity at the mMC1R. The compound EL1 with racemic Nal(2') in the i + 1 position, DPro in the i + 2 position, and Trp in the i + 3 position possesses an EC(50) of 42.5 +/- 6.9 microM. Compound EL2 with Trp in the i + 1 position, DLys in the i + 2 position, and Phe in the i + 3 position possesses an EC(50) value of 63.4 +/- 26.9 microM. The results of the library screening process are consistent with a hypothesis dating back to the 1980s proposing that a beta-turn conformation involving the melanocortin "Phe-Arg-Trp" core amino acids provides the key recognition element. Additionally, these compounds represent the first nonpeptidic heterocyclic molecules reported to date that are able to activate the MC1R, a melanocyte receptor involved in skin pigmentation and animal coat coloration.
Assuntos
Oligopeptídeos/química , Receptores da Corticotropina/química , Animais , Células Cultivadas , Desenho de Fármacos , Ligantes , Camundongos , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Estrutura Secundária de Proteína , Receptores da Corticotropina/agonistas , Receptores da Corticotropina/biossíntese , Receptores de Melanocortina , Relação Estrutura-AtividadeRESUMO
A library of 2302 small molecule beta-turn mimetics was screened for inhibition of the alpha 4 beta 1 integrin-CS1 splice variant binding interaction. Preliminary data revealed several active ligands, and validation with purified material culminated in the identification of some of the first small molecule ligands (1, IC50 = 5 microM, and 2, IC50 = 8 microM) to be reported for this class of integrins.