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1.
Nat Rev Chem ; 7(1): 3-4, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37117823
3.
Bioorg Med Chem Lett ; 50: 128352, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34481987

RESUMO

Activation of the PI3K/Akt/mTOR kinase pathway is associated with human cancers. A dual p70S6K/Akt inhibitor is sufficient to inhibit strong tumor growth and to block negative impact of the compensatory Akt feedback loop activation. A scaffold docking strategy based on an existing quinazoline carboxamide series identified 4-aminopyrimidine analog 6, which showed a single-digit nanomolar and a micromolar potencies in p70S6K and Akt enzymatic assays. SAR optimization improved Akt enzymatic and p70S6K cellular potencies, reduced hERG liability, and ultimately discovered the promising candidate 37, which exhibited with a single digit nanomolar value in both p70S6K and Akt biochemical assays, and hERG activities (IC50 = 17.4 µM). This agent demonstrated dose-dependent efficacy in inhibiting mice breast cancer tumor growth and covered more than 90% pS6 inhibition up to 24 h at a dose of 200 mg/kg po.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Mamárias Animais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Área Sob a Curva , Cães , Feminino , Meia-Vida , Haplorrinos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
4.
J Med Chem ; 62(17): 7643-7655, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31368705

RESUMO

Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Descoberta de Drogas , Doenças do Sistema Imunitário/tratamento farmacológico , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Administração Oral , Tirosina Quinase da Agamaglobulinemia/metabolismo , Relação Dose-Resposta a Droga , Humanos , Doenças do Sistema Imunitário/metabolismo , Estrutura Molecular , Piperidinas/administração & dosagem , Piperidinas/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Relação Estrutura-Atividade
5.
Angew Chem Int Ed Engl ; 57(16): 4412-4428, 2018 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-28971564

RESUMO

Immuno-oncology therapies have the potential to revolutionize the armamentarium of available cancer treatments. To further improve clinical response rates, researchers are looking for novel combination regimens, with checkpoint blockade being used as a backbone of the treatment. This Review highlights the significance of small molecules in this approach, which holds promise to provide increased benefit to cancer patients.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Humanos , Neoplasias/patologia
6.
Bioorg Med Chem Lett ; 27(13): 2838-2848, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28506751

RESUMO

The frequency of PI3K/Akt/mTOR (PAM) Pathway mutations in human cancers sparked interest to determine if the pathway is druggable. The modest clinical benefit observed with mTOR rapalogs (temsirolimus and everolimus) provided further motivation to identify additional nodes of pathway inhibition that lead to improved clinical benefit. Akt is a central signaling node of the PAM pathway and could be an ideal target for improved pathway inhibition. Furthermore, inhibitors of Akt may be especially beneficial in tumors with Akt1 mutations. Recently, multiple ATP-competitive Akt inhibitors have been identified and are currently in clinical development. This review details the medicinal chemistry efforts towards identification of these molecules, highlights relevant preclinical data supporting clinical evaluation, and summarizes current clinical development plans.


Assuntos
Trifosfato de Adenosina/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/farmacologia , Trifosfato de Adenosina/síntese química , Trifosfato de Adenosina/química , Animais , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
7.
Am J Cancer Res ; 6(4): 806-18, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27186432

RESUMO

Dysregulated PI3K/Akt/mTOR (PAM) pathway signaling occurs in ~30% of human cancers, making it a rational target for new therapies; however, the effectiveness of some PAM pathway inhibitors, such as mTORC rapalogs, may be compromised by a compensatory feedback loop leading to Akt activation. In this study, the p70S6K/Akt dual inhibitor, M2698 (previously MSC2363318A), was characterized as a potential anti-cancer agent through examination of its pharmacokinetic, pharmacodynamic and metabolic properties, and anti-tumor activity. M2698 was highly potent in vitro (IC50 1 nM for p70S6K, Akt1 and Akt3 inhibition; IC50 17 nM for pGSK3ß indirect inhibition) and in vivo (IC50 15 nM for pS6 indirect inhibition), and relatively selective (only 6/264 kinases had an IC50 within 10-fold of p70S6K). Orally administered M2698 crossed the blood-brain barrier in rats and mice, with brain tumor exposure 4-fold higher than non-disease brain. Dose-dependent inhibition of target substrate phosphorylation was observed in vitro and in vivo, indicating that M2698 blocked p70S6K to provide potent PAM pathway inhibition while simultaneously targeting Akt to overcome the compensatory feedback loop. M2698 demonstrated dose-dependent tumor growth inhibition in mouse xenograft models derived from PAM pathway-dysregulated human triple-negative (MDA-MB-468) and Her2-expressing breast cancer cell lines (MDA-MB-453 and JIMT-1), and reduced brain tumor burden and prolonged survival in mice with orthotopically implanted U251 glioblastoma. These findings highlight M2698 as a promising PAM pathway inhibitor whose unique mechanism of action and capacity to pass the blood-brain barrier warrant clinical investigation in cancers with PAM pathway dysregulation, and those with central nervous system involvement.

8.
Protein Sci ; 22(3): 274-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23238807

RESUMO

The introduction of non-natural modules could provide unprecedented control over folding/unfolding behavior, conformational stability, and biological function of proteins. Success requires the interrogation of candidate modules in natural contexts. Here, expressed protein ligation is used to replace a reverse turn in bovine pancreatic ribonuclease (RNase A) with a synthetic ß-dipeptide: ß²-homoalanine-ß³-homoalanine. This segment is known to adopt an unnatural reverse-turn conformation that contains a 10-membered ring hydrogen bond, but one with a donor-acceptor pattern opposite to that in the 10-membered rings of natural reverse turns. The RNase A variant has intact enzymatic activity, but unfolds more quickly and has diminished conformational stability relative to native RNase A. These data indicate that hydrogen-bonding pattern merits careful consideration in the selection of beneficial reverse-turn surrogates.


Assuntos
Aminobutiratos/química , Dipeptídeos/química , Fragmentos de Peptídeos/química , Ribonuclease Pancreático/química , Animais , Asparagina/análogos & derivados , Asparagina/química , Bovinos , Dicroísmo Circular , Dipeptídeos/genética , Dipeptídeos/metabolismo , Estabilidade Enzimática , Ligação de Hidrogênio , Cinética , Ácidos Nipecóticos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Prolina/análogos & derivados , Prolina/química , Processamento de Proteína , Estrutura Secundária de Proteína , Desdobramento de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/metabolismo , Estereoisomerismo , Temperatura de Transição
9.
Bioorg Med Chem Lett ; 16(15): 4130-4, 2006 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16750364

RESUMO

5-HT2C agonists have shown efficacy in limiting food consumption and thus may serve as an important drug class in combating obesity. We describe the design and synthesis of a novel tricyclic single-nitrogen scaffold that was used to produce 5-HT2C agonists. SAR was developed around this chemotype and compounds were identified that were potent (Ki<15 nM) and selective relative to other 5-HT2 receptors. The most promising compound displayed a good pharmacokinetic profile in multiple animal species, and was efficacious in an acute feeding study in rats.


Assuntos
Nitrogênio/química , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/farmacologia , Animais , Cães , Desenho de Fármacos , Comportamento Alimentar/efeitos dos fármacos , Meia-Vida , Ratos , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 16(11): 2891-4, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16546379

RESUMO

The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.


Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina , Aminas/química , Animais , Compostos Aza/síntese química , Compostos Bicíclicos com Pontes/síntese química , Estrutura Molecular , Pirimidinas/síntese química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
11.
J Org Chem ; 70(9): 3353-62, 2005 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-15844969

RESUMO

[reaction: see text] We have recently shown that members of a new class of beta-peptides, containing 2,2-disubstituted pyrrolidine-4-carboxylic acid residues, display discrete conformational preferences despite the impossibility of internal hydrogen bonding (Huck et al. J. Am. Chem. Soc. 2003, 125, 9035). Here we describe the synthesis of a variety of 2,2-disubstituted pyrrolidine-4-carboxylic derivatives that bear a diverse set of side chains and protecting groups suitable for oligomer synthesis. In addition, we discuss coupling methods for construction of oligomers in solution and on solid phase. Non-hydrogen bonded foldamers such as those generated from 2,2-disubstituted pyrrolidine-4-carboxylic acids may be useful in biomedical applications because the low intrinsic polarity of their backbones may promote bioavailability.


Assuntos
Ácidos Carboxílicos/síntese química , Técnicas de Química Combinatória , Oligopeptídeos/química , Pirrolidinas/síntese química , Dimerização , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Estrutura Secundária de Proteína
12.
J Am Chem Soc ; 125(30): 9035-7, 2003 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-15369358

RESUMO

We examine a new class of beta-peptides, 2,2-disubstituted pyrrolidine-4-carboxylic acid oligomers, and show that they manifest discrete conformational preferences despite the impossibility of internal hydrogen bonding. Numerous beta-peptide families have been described that display specific secondary structural preferences, but all of the conformations characterized in detail so far have contained internal hydrogen bonds. Internal hydrogen bonding is observed within the most common secondary structures of conventional peptides as well. Identifying foldamers in which shape control is independent of hydrogen bonding is significant in two ways. At a fundamental level, foldamers in this small but growing class are interesting because their shapes are controlled by distinctive networks of noncovalent forces. At a practical level, non-hydrogen bonded foldamers may be useful in biomedical applications because the low intrinsic polarity of their backbones may promote bioavailability.


Assuntos
Oligopeptídeos/química , Pirrolidinas/química , Ácidos Carboxílicos/química , Dicroísmo Circular , Dimerização , Ligação de Hidrogênio , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Dobramento de Proteína , Estrutura Secundária de Proteína
13.
Biochemistry ; 41(42): 12835-42, 2002 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-12379126

RESUMO

Protegrins are short, cationic peptides that display potent, broad-spectrum antimicrobial activity. PG-1, the first of the five natural analogues discovered, forms a rigid antiparallel two-stranded beta-sheet that is stabilized by two disulfide bonds. The two strands of the sheet are linked by a short two-residue loop segment. Removal of the disulfide bridges (e.g., in Cys --> Ala analogues) is known to cause marked loss of antimicrobial activity. We have used basic principles of beta-hairpin design to develop linear analogues of PG-1 that lack cysteine but nevertheless display PG-1-like activity. Our most potent reengineered molecules contain three essential design features: (i) the four cysteine residues of PG-1 are replaced by residues that have high propensity for beta-strand conformation, (ii) D-proline is placed at the i + 1 position of the reverse turn to promote a type II' beta-turn, and (iii) amino functionality is incorporated at the gamma-carbon of the D-proline residue to mimic the charge distribution of the natural beta-hairpin. Structural studies revealed that the antimicrobial potency of the non-disulfide-bonded peptides can be correlated to the stability of the beta-hairpin conformations they adopt in aqueous solution. The presence of 150 mM NaCl was found to have little effect on the antimicrobial activity of PG-1, but one of our linear analogues loses some potency under these high salt conditions. Despite this discrepancy in salt sensitivity, NMR and CD data indicate that neither PG-1 nor our linear analogue experiences a significant decrease in beta-hairpin conformational stability in the presence of 150 mM NaCl. Thus, salt inactivation is not due to destabilization of the beta-hairpin conformation. Furthermore, our results show that beta-sheet design principles can be used to replace conformation-stabilizing disulfide bridges with noncovalent conformation-stabilizing features.


Assuntos
Antibacterianos/síntese química , Peptídeos Catiônicos Antimicrobianos/síntese química , Cisteína/química , Proteínas/síntese química , Sequência de Aminoácidos , Animais , Antibacterianos/isolamento & purificação , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/crescimento & desenvolvimento , Dicroísmo Circular , Dissulfetos/química , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/crescimento & desenvolvimento , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Dados de Sequência Molecular , Conformação Proteica , Isoformas de Proteínas/síntese química , Isoformas de Proteínas/isolamento & purificação , Estrutura Secundária de Proteína , Proteínas/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-Atividade , Suínos
14.
J Am Chem Soc ; 124(29): 8522-3, 2002 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-12121081

RESUMO

beta-Amino acids are incorporated into an enzyme by using the method of expressed protein ligation. In the resulting semisynthetic enzyme, an R-nipecotic acid-S-nipecotic acid module replaces Asn113 and Pro114 of ribonuclease A. The semisynthetic enzyme not only retains full catalytic activity but also gains conformational stability. Thus, structural elements can be replaced with foldameric equivalents to endow proteins with more desirable properties.


Assuntos
Ribonuclease Pancreático/síntese química , Catálise , Dobramento de Proteína , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ribonuclease Pancreático/química
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