Platforms for high-throughput screening of Wnt/Frizzled antagonists

Koval, Alexey; Katanaev, Vladimir L.

doi:10.1016/j.drudis.2012.07.007

Cited by 29 publications

(33 citation statements)

References 77 publications

(124 reference statements)

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“…Despite the differences that SMO mediates hedgehog signaling and FZD 6 mediates WNT signaling, both are characterized by their ability to couple to and activate heterotrimeric G i proteins 15,[18][19][20][21] , and their inability to signal via the WNT/β-catenin pathway 22,23 . FZD 6 and SMO are both characterized by a long TM6 extending above the plasma membrane toward the CRD 15,[24][25][26] and the longest C-terminal domains across Class F receptors (SMO: 250 aa; FZD 6 : 211 aa). Thus, the similarities of FZD 6 and SMO compared to FZD 4 provided the basis of our efforts of reprofiling SMO agonists for FZD 6 .…”

Section: Resultsmentioning

confidence: 99%

“…While there are several small molecules available that target SMO as agonists (SAG1.3, SAG1.5, and purmorphamine), inverse agonists (cyclopamine-KAAD), and neutral antagonists (vismodegib and SANT-1), no small molecules with clear-cut pharmacology have been identified targeting any FZD. Given their involvement in pathology, FZDs harbor a huge therapeutic potential and therefore, drugging FZDs has attracted substantial attention [4][5][6] . Interestingly, the crystal structure of FZD 4 , which presents a ligand-free receptor inferred that development of small molecules targeting the core of FZDs can be virtually impossible given the hydrophilic nature of the binding pocket 7 , a notion that has previously been challenged 8 .…”

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confidence: 99%

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Structural insight into small molecule action on Frizzleds

et al. 2020

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WNT-Frizzled (FZD) signaling plays a critical role in embryonic development, stem cell regulation and tissue homeostasis. FZDs are linked to severe human pathology and are seen as a promising target for therapy. Despite intense efforts, no small molecule drugs with distinct efficacy have emerged. Here, we identify the Smoothened agonist SAG1.3 as a partial agonist of FZD 6 with limited subtype selectivity. Employing extensive in silico analysis, resonance energy transfer-and luciferase-based assays we describe the mode of action of SAG1.3. We define the ability of SAG1.3 to bind to FZD 6 and to induce conformational changes in the receptor, recruitment and activation of G proteins and dynamics in FZD-Dishevelled interaction. Our results provide the proof-of-principle that FZDs are targetable by small molecules acting on their seven transmembrane spanning core. Thus, we provide a starting point for a structure-guided and mechanism-based drug discovery process to exploit the potential of FZDs as therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Structural insight into small molecule action on Frizzleds

et al. 2020

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“…Frizzleds (FZDs) regulate a number of processes during embryonic development, stem cell regulation, and adult tissue homeostasis. Deregulation or misexpression of FZDs leads to pathogenesis, including, but not limited to, cancer and neurologic disorders; thus, making them attractive drug targets 8, 9 . In mammals, there are 10 Frizzleds (FZD 1–10 ), which are activated by the WNT family of lipoglycoproteins through interaction with the N-terminal cysteine-rich domain (CRD) of FZD 10, 11 .…”

Section: Introductionmentioning

confidence: 99%

Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling

et al. 2017

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G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD6 dimerizes and that the dimer interface of FZD6 is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD6 mutant indicates that dimer dissociation is an integral part of FZD6 signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.

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“…A recent screen with FZD internalization as readout has identified the antihelminthic drug niclosamide, even though the molecular mechanism and direct action through FZD remains elusive (Chen et al ., ). Thus, more appropriate screening technologies could aid the development of FZD targeting molecules, so providing useful research tools and therapeutics (Koval and Katanaev, ).…”

Section: Introductionmentioning

confidence: 99%

WNT/Frizzled signalling: receptor–ligand selectivity with focus on FZD‐G protein signalling and its physiological relevance: IUPHAR Review 3

Dijksterhuis

Petersen

Schulte

2014

British J Pharmacology

169

144

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The wingless/int1 (WNT)/Frizzled (FZD) signalling pathway controls numerous cellular processes such as proliferation, differentiation, cell‐fate decisions, migration and plays a crucial role during embryonic development. Nineteen mammalian WNTs can bind to 10 FZDs thereby activating different downstream pathways such as WNT/β‐catenin, WNT/planar cell polarity and WNT/Ca2+. However, the mechanisms of signalling specification and the involvement of heterotrimeric G proteins are still unclear. Disturbances in the pathways can lead to various diseases ranging from cancer, inflammatory diseases to metabolic and neurological disorders. Due to the presence of seven‐transmembrane segments, evidence for coupling between FZDs and G proteins and substantial structural differences in class A, B or C GPCRs, FZDs were grouped separately in the IUPHAR GPCR database as the class FZD within the superfamily of GPCRs. Recently, important progress has been made pointing to a direct activation of G proteins after WNT stimulation. WNT/FZD and G protein coupling remain to be fully explored, although the basic observation supporting the nature of FZDs as GPCRs is compelling. Because the involvement of different (i) WNTs; (ii) FZDs; and (iii) intracellular binding partners could selectively affect signalling specification, in this review we present the current understanding of receptor/ligand selectivity of FZDs and WNTs. We pinpoint what is known about signalling specification and the physiological relevance of these interactions with special emphasis on FZD–G protein interactions. Linked Articles This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5

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Platforms for high-throughput screening of Wnt/Frizzled antagonists

Cited by 29 publications

References 77 publications

Structural insight into small molecule action on Frizzleds

Structural insight into small molecule action on Frizzleds

Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling

WNT/Frizzled signalling: receptor–ligand selectivity with focus on FZD‐G protein signalling and its physiological relevance: IUPHAR Review 3

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