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A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function
Vincent Fagan1,2, Catrine Johansson1,3, Carina Gileadi1,3
1Structural Genomics Consortium, Nuffield Department of Medicine , University of Oxford , OX3 7DQ Oxford , U.K.
Journal of Medicinal Chemistry
|September 25, 2019
Summary
Researchers developed a chemical probe inhibitor for spindlin1 (SPIN1), a protein involved in gene regulation. This inhibitor shows high selectivity and cellular activity, offering new insights into SPIN1
Area of Science:
- Epigenetics and Molecular Biology
- Cancer Research
- Chemical Biology
Background:
- Histone modifications, such as lysine/arginine methylation, form a 'chromatin code' interpreted by 'reader' proteins.
- Spindlin1 (SPIN1) is a protein with Tudor methyllysine/arginine reader domains, implicated as a potential oncogene and transcriptional coactivator.
- Understanding the function of SPIN1 is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To develop and characterize a selective chemical probe inhibitor for the spindlin1 (SPIN1) protein.
- To investigate the molecular mechanism of SPIN1 inhibition using X-ray crystallography.
- To identify genes regulated by SPIN1 and explore its role in squamous cell carcinoma.
Main Methods:
- Development of a SPIN1 chemical probe inhibitor with high in vitro and cellular activity.
- X-ray crystallography to determine the binding mode of the inhibitor to SPIN1 Tudor domains.
- Small molecule inhibition, siRNA knockdown, and chemoproteomic studies to identify SPIN1-regulated genes.
- Analysis of SPIN1's role in squamous cell carcinoma, including cancer-related inflammation and metastasis.
Main Results:
- A SPIN1 chemical probe inhibitor was synthesized with low nanomolar in vitro activity and submicromolar cellular activity.
- The inhibitor demonstrated exquisite selectivity for SPIN1's Tudor domains, binding simultaneously to domains 1 and 2.
- Identification of genes transcriptionally regulated by SPIN1 in squamous cell carcinoma.
- Evidence suggesting SPIN1's involvement in cancer-related inflammation and/or metastasis.
Conclusions:
- A potent and selective chemical probe for SPIN1 has been developed, enabling functional studies.
- The inhibitor's bidentate binding mode to SPIN1 Tudor domains provides structural insights for drug design.
- SPIN1 plays a role in regulating genes in squamous cell carcinoma, potentially influencing cancer progression and metastasis.
