RESUMO
Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman's Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology.
Assuntos
Interleucina-6/antagonistas & inibidores , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Desenho de Fármacos , Meia-Vida , Humanos , Hibridomas , Interleucina-6/química , Interleucina-6/metabolismo , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Modelos Moleculares , Dados de Sequência Molecular , Biblioteca de Peptídeos , Peptídeos/química , Peptídeos/metabolismo , Conformação Proteica , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-6/química , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Células U937RESUMO
We have designed and synthesized a series of structurally novel hydroxamic acid-based histone deacetylase (HDAC) inhibitors characterized by a zinc chelating head group attached directly to a thiazole ring. The thiazole ring connects to a piperazine spacer, which is capped with a sulfonamide group. These novel molecules potently inhibit an HDAC enzyme mixture derived from HeLa cervical carcinoma cells and show potent antiproliferative activity against the breast cancer cell line MCF7.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Células HeLa , Humanos , Ácidos Hidroxâmicos/síntese química , Relação Estrutura-AtividadeRESUMO
Inhibitors of histone deacetylases (HDAC) are emerging as a promising class of anti-cancer agents. A mercaptoamide functionality was designed as a bidentate zinc chelator and incorporated into the hydroxamic acid based SAHA (1) scaffold in order to identify non-hydroxamate compounds as potential inhibitors of histone deacetylases. Two sets of mercaptoamides 2 and 3 with varying spacer length were synthesized and their HDAC inhibitory activity was evaluated. Low micromolar inhibition was observed for mercaptoamides 2e, 3b, and 3d.
Assuntos
Amidas/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/classificação , Inibidores de Histona Desacetilases , Compostos de Sulfidrila/química , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/químicaRESUMO
Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P(1)' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P(1)' site. Compounds with MICs of