RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/patologia , Fragmentos de Peptídeos/metabolismo , Pirazinas/farmacologia , Sialoglicoproteínas/metabolismo , Triazinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Genes APC , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Pirazinas/uso terapêutico , Sialoglicoproteínas/antagonistas & inibidores , Triazinas/uso terapêutico , Via de Sinalização Wnt/genética , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , beta Catenina/antagonistas & inibidoresRESUMO
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.