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1.
Cancer Res ; 81(4): 1052-1062, 2021 02 15.
Article in English | MEDLINE | ID: mdl-33408116

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/pathology , Peptide Fragments/metabolism , Pyrazines/pharmacology , Sialoglycoproteins/metabolism , Triazines/pharmacology , Wnt Signaling Pathway/drug effects , beta Catenin/metabolism , Animals , Antineoplastic Agents/therapeutic use , Cell Proliferation/drug effects , Cells, Cultured , Disease Models, Animal , Female , Genes, APC , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Nude , Mice, Transgenic , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Peptide Fragments/antagonists & inhibitors , Protein Binding/drug effects , Pyrazines/therapeutic use , Sialoglycoproteins/antagonists & inhibitors , Triazines/therapeutic use , Wnt Signaling Pathway/genetics , Wnt1 Protein/genetics , Wnt1 Protein/metabolism , beta Catenin/antagonists & inhibitors
2.
F1000Res ; 4: 75, 2015.
Article in English | MEDLINE | ID: mdl-25949808

ABSTRACT

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.

3.
Org Lett ; 15(7): 1686-9, 2013 Apr 05.
Article in English | MEDLINE | ID: mdl-23528142

ABSTRACT

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.


Subject(s)
Cyclopropanes/chemical synthesis , Oligopeptides/chemical synthesis , Peptidomimetics/chemical synthesis , Amino Acid Sequence , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Humans , Models, Molecular , Oligopeptides/chemistry , Oligopeptides/pharmacology , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Protein Structure, Secondary , Receptor, Melanocortin, Type 4/metabolism , Stereoisomerism
4.
Bioorg Med Chem ; 17(18): 6742-7, 2009 Sep 15.
Article in English | MEDLINE | ID: mdl-19695883

ABSTRACT

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.


Subject(s)
Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/metabolism , Urotensins/chemistry , Amino Acid Sequence , Cell Line , Humans , Models, Molecular , Molecular Conformation , Peptide Library
6.
Chem Pharm Bull (Tokyo) ; 57(2): 211-3, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19182415

ABSTRACT

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.


Subject(s)
Ethylenediamines/chemistry , Indoles/chemistry , Tryptophan/chemistry , Chromatography, High Pressure Liquid , Formates/chemistry , Indicators and Reagents , Peptides/chemical synthesis , Peptides/chemistry , Solutions/analysis , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Ultraviolet , Water/analysis
7.
Bioorg Med Chem Lett ; 16(14): 3723-6, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16678415

ABSTRACT

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.


Subject(s)
Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Receptor, Melanocortin, Type 4/agonists , Amino Acid Sequence , Circular Dichroism , Drug Design , Humans , Lactams/chemistry , Lactams/pharmacology , Molecular Sequence Data , Protein Binding , Receptor, Melanocortin, Type 1/agonists , Receptor, Melanocortin, Type 1/metabolism , Receptor, Melanocortin, Type 4/metabolism , Structure-Activity Relationship , alpha-MSH/metabolism
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