Chemical Genetics Reveals a Role of dCTP Pyrophosphatase 1 in Wnt Signaling

Abstract

Cell-based screening is ap owerfula pproach to identify novel chemical modulators and biological components of relevant biological processes.The canonical Wnt pathway is essential for normal embryonic development and tissue homeostasis,a nd its deregulation playsacrucial role in carcinogenesis.T herefore,t he identification of new pathway members and regulators is of significant interest. By means of ac ell-based assaym onitoring Wnt signaling we identified the pyrrolocoumarin Pyrcoumin as inhibitor of canonical Wnt signaling.T arget identification and validation revealed that Pyrcoumin is ac ompetitive inhibitor of dCTP pyrophosphatase 1(dCTPP1). We demonstrate ayet unknown interaction of dCTPP1 with ubiquitin carboxyl-terminal hydrolase (USP7) that is counteracted by dCTPP1 inhibitors.T hese findings indicate that dCTPP1 playsarole in regulation of Wnt/bcatenin signaling most likely through ad irect interaction with USP7.

Identification of a Novel Pseudo‐Natural Product Type IV IDO1 Inhibitor Chemotype

“…Exchange of the nosyl group with other sulphonamides gave high yields and good enantioselectivity (Table 1, entries 5-12. but the reaction failed with N-o-nitrophenyl ketimine. Various allenoates reacted successfully with ketimine 1 a and provided the desired products in moderate to high yields with good enantioselectivity (Table 1, entries [13][14][15][16][17][18]. However, attempts to displace esters at R 3 with H, an alkyl moiety, e.g.…”

“…The pseudo-NP collection was investigated in different cell-based assays to evaluate their influence on various biological pathways, e.g. Wnt, [14] Notch and Hedgehog (Hh) signalling, [15] autophagy, [3b, 16] and modulation of kynurenine (Kyn) levels. [9c] Apoxidole derivative (S,R)-3 b (Table 1, entry 2) selectively decreased cellular kynurenine (Kyn) levels in BxPC-3 cells (Figure S1) upon stimulation with the cytokine Interferon-γ (IFN-γ).…”

Identification of Novel Target DCTPP1 for Colorectal Cancer Therapy with the Natural Small-molecule Inhibitors Regulating Metabolic Reprogramming

“…[8] Moreover, DCTPP1 is a typical positive regulator of the Wnt pathway, which is crucial for embryonic development and cell proliferation. [9] Besides, as an important part of nucleotide metabolism, DCTPP1 might affect energy metabolism, including amino acid metabolism. [10] Currently, only a few of DCTPP1 inhibitors have been reported, including triptolide, terpenoid epoxide, benzimidazole, and triazolothiadiazole.…”