RESUMEN
The Wnt/ß-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between ß-catenin and CREB binding protein, which is part of the Wnt/ß-catenin signaling pathway, disrupts the Wnt/ß-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin /+ mice, in which mutation of Apc activates the Wnt/ß-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/ß-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/ß-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias/patología , Fragmentos de Péptidos/metabolismo , Pirazinas/farmacología , Sialoglicoproteínas/metabolismo , Triazinas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Animales , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Genes APC , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones Transgénicos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fragmentos de Péptidos/antagonistas & inhibidores , Unión Proteica/efectos de los fármacos , Pirazinas/uso terapéutico , Sialoglicoproteínas/antagonistas & inhibidores , Triazinas/uso terapéutico , Vía de Señalización Wnt/genética , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , beta Catenina/antagonistas & inhibidoresRESUMEN
In a previous Method Article, we have presented the 'Structure-Activity Relationship (SAR) Matrix' (SARM) approach. The SARM methodology is designed to systematically extract structurally related compound series from screening or chemical optimization data and organize these series and associated SAR information in matrices reminiscent of R-group tables. SARM calculations also yield many virtual candidate compounds that form a "chemical space envelope" around related series. To further extend the SARM approach, different methods are developed to predict the activity of virtual compounds. In this follow-up contribution, we describe an activity prediction method that derives conditional probabilities of activity from SARMs and report representative results of first prospective applications of this approach.
RESUMEN
Conformationally restricted peptidomimetics comprising eight stereoisomeric scaffolds with three-dimensional structural diversity were designed based on the structural features of cyclopropane, that is, cyclopropylic strain, which mimic wide-ranging tetrapeptide conformations covering ß-turns through ß-strands. Stereoselective synthesis of the designed peptidomimetics led to the identification of nonpeptidic melanocortin-4 receptor ligands.
Asunto(s)
Ciclopropanos/síntesis química , Oligopéptidos/síntesis química , Peptidomiméticos/síntesis química , Secuencia de Aminoácidos , Ciclopropanos/química , Ciclopropanos/farmacología , Humanos , Modelos Moleculares , Oligopéptidos/química , Oligopéptidos/farmacología , Peptidomiméticos/química , Peptidomiméticos/farmacología , Estructura Secundaria de Proteína , Receptor de Melanocortina Tipo 4/metabolismo , EstereoisomerismoRESUMEN
Urotensin-II (UT-II) is thought to be involved in the regulation of cardiovascular homeostasis and pathology. A head-to-tail cyclic hexapeptide library based on UT-II sequence was designed, synthesized, and evaluated by the activity on the UT-II receptor (GPR-14). A new synthetic sequence, WK[Xaa] (Xaa: amino acid with aromatic side chain), was identified as a characteristic minimum fragment activating hUT-II receptor instead of the WK[Y] sequence. Compound 1 showed an agonistic activity with an EC(50) value of 6.94 nM. The conformational investigation suggested that 1 did not have typical secondary structure in the message sequence. Structural analyses may enable us to investigate the active conformation of UT-II and lead to the identification of new ligands for GPR-14.
Asunto(s)
Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Urotensinas/química , Secuencia de Aminoácidos , Línea Celular , Humanos , Modelos Moleculares , Conformación Molecular , Biblioteca de PéptidosAsunto(s)
Etilenodiaminas/química , Indicadores y Reactivos/química , Triptófano/química , Soluciones , AguaRESUMEN
The deprotection of the indole (N(ind))-formyl (For) group on Trp was achieved in a 95% yield using N,N'-dimethylethylendiamine (DMEDA) (1.5, 2.0, 3.0 eq) in water at room temperature. A new reagent was successfully applied to the deprotection of a model peptide, H-Phe-Trp(N(ind)-For)-Lys-Tyr-OH, to give H-Phe-Trp-Lys-Tyr-OH in a 91% yield.
Asunto(s)
Etilenodiaminas/química , Indoles/química , Triptófano/química , Cromatografía Líquida de Alta Presión , Formiatos/química , Indicadores y Reactivos , Péptidos/síntesis química , Péptidos/química , Soluciones/análisis , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta , Agua/análisisRESUMEN
A series of cyclic pentapeptides, c(His-D-Phe-Arg-Trp-Z) (Z=omega-amino acid), were prepared and biologically evaluated. The effects of increasing alkyl chain length of omega-amino acid on the functional activities and the receptor binding affinities for human melanocortin receptors (hMC-Rs) were studied. Compound 2 was an agonist for hMC-4R with an EC50 value of 15.4 nM, which was 4.7 times more potent than that of alpha-MSH. Compound 2 also showed a 4.3-fold higher hMC-4R selectivity over hMC-1R, thus providing us with information concerning size and chemical structure of the lactam ring for the development of the agonist with hMC-4R selectivity.