The small GTPases of the ADP-ribosylation factors (ARFs) regulate signaling pathways by switching between active (GTP-bound) and inactive (GDP-bound) forms. Two types of proteins tightly regulate the signaling activity of small GTPases: (a) Guanine nucleotide exchange factor (GEF) proteins promote GDP–GTP exchange and activate signaling and (b) GTPase-activating proteins (GAPs) stimulate the intrinsic GTP hydrolyzing activity of G proteins to inhibit signaling.<br/>Wnt family of secreted glycoproteins act as a short- or long-range signaling molecule via a key mediator and a transcription co-activator beta-catenin. It has been previously reported that activation of Arf is essential for Wnt/beta-catenin signaling.<br/>ARF family of proteins and Wnt/beta-catenin signaling pathways are known to direct various biological processes, including cell development, homeostasis, and fate. It has been shown that a small molecule (QS11) inhibits the GTPase-activating protein of ADP-ribosylation factor1 (Arf1), ArfGAP1, and is a Wnt synergist. Indicating the role of ArfGap1 in Wnt/beta-catenin signaling. But it was not clear if only inhibition of ArfGAP1 by QS11 leads to the activation of Wnt/beta-catenin signal transduction. Also, direct inhibition of ARFGAP1 by QS11 was not been established. We studied SAR of QS11 analogs in two assays: (a) direct inhibition of purified ARFGAP1 protein and (b) cellular activation of the Wnt/b-catenin pathway. Overall, our data suggest that QS11 has other potential targets in cells and confirms direct inhibition of ARFGAP1 by QS11.

Structure-activity relationship studies of a small molecule, QS11, an ARFGAP1 inhibitor

ACS Fall 2021

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