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Target Deconvolution Efforts on Wnt Pathway Screen Reveal Dual Modulation of Oxidative Phosphorylation and SERCA2
Matias Casás-Selves1,2, Andrew X Zhang3, James E Dowling1
1Oncology, Innovative Medicines and Early Discovery Unit, AstraZeneca, 35 Gatehouse Drive, Waltham, MA, 02451, USA.
Chemmedchem
|April 4, 2017
Summary
This study identifies a new chemical series that inhibits cancer-linked Wnt signaling by disrupting ATP synthesis and targeting the SERCA2 protein. These 1,2,3-thiadiazole-5-carboxamides act as ionophores, impacting cellular energy production.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Wnt signaling is crucial for cellular processes and its dysregulation is linked to cancer.
- A Wnt-pathway screen identified 1,2,3-thiadiazole-5-carboxamides (TDZ) as potent inhibitors.
- The precise mechanism of action for this TDZ chemical series was previously unknown.
Purpose of the Study:
- To elucidate the mechanism of action of the TDZ chemical series.
- To identify the specific molecular targets responsible for TDZ's efficacy.
- To understand the biological implications of TDZ engagement with its targets.
Main Methods:
- Utilized bottom-up quantitative chemoproteomics to identify binding partners.
- Employed cell biology and biochemical assays to validate target engagement and functional effects.
- Investigated the impact of TDZ compounds on cellular metabolism and mitochondrial potential.
Main Results:
- The TDZ series was found to inhibit ATP synthesis by uncoupling mitochondrial membrane potential.
- Affinity chemoproteomics identified sarco(endo)plasmic reticulum Ca2+-dependent ATPase (SERCA2) as a direct binding partner.
- TDZ compounds function as ionophores through SERCA2, leading to Wnt pathway inhibition.
Conclusions:
- The TDZ chemical series inhibits Wnt signaling through a novel mechanism involving SERCA2 ionophore activity.
- This mechanism disrupts cellular energy homeostasis by inhibiting ATP production.
- The findings provide a deeper understanding of Wnt pathway regulation and potential therapeutic strategies for cancers driven by Wnt pathway activation.