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Identification of pyrimidine derivatives as hSMG-1 inhibitors
Ariamala Gopalsamy1, Eric M Bennett, Mengxiao Shi
1Worldwide Medicinal Chemistry, Pfizer, 200 Cambridgepark Drive, Cambridge, MA 02140, USA. ariamala.gopalsamy@pfizer.com
Abstract:
hSMG-1 kinase plays a dual role in a highly conserved RNA surveillance pathway termed nonsense-mediated RNA decay (NMD) and in cellular genotoxic stress response. Since deregulation of cellular responses to stress contributes to tumor growth and resistance to chemotherapy, hSMG-1 is a potential target for cancer treatment. From our screening efforts, we have identified pyrimidine derivatives as hSMG-1 kinase inhibitors. We report structure-based optimization of this pan-kinase scaffold to improve its biochemical profile and overall kinome selectivity, including mTOR and CDK, to generate the first reported selective hSMG-1 tool compound.
Insights
Researchers identified pyrimidine derivatives as inhibitors of hSMG-1 kinase, crucial in RNA decay and stress response. Optimized compounds offer a selective tool for cancer therapy research.
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- The hSMG-1 kinase is integral to the nonsense-mediated RNA decay (NMD) pathway and cellular genotoxic stress responses.
- Dysregulation of stress response pathways is implicated in tumor progression and chemoresistance, highlighting hSMG-1 as a potential therapeutic target.
Purpose of the Study:
- To identify and optimize inhibitors of hSMG-1 kinase for potential cancer treatment applications.
- To develop a selective chemical probe for studying hSMG-1 function in biological systems.
Main Methods:
- High-throughput screening to identify initial pyrimidine-based hSMG-1 inhibitors.
- Structure-based drug design for optimizing kinase inhibitor potency and selectivity.
- Biochemical assays to assess kinome selectivity against targets like mTOR and CDK.
Main Results:
- Identification of pyrimidine derivatives as potent hSMG-1 kinase inhibitors.
- Structure-based optimization led to improved biochemical profiles and enhanced selectivity.
- Generation of the first reported selective small-molecule tool compound targeting hSMG-1.
Conclusions:
- Selective hSMG-1 inhibitors, derived from pyrimidine scaffolds, represent a promising avenue for cancer therapy development.
- The novel selective hSMG-1 tool compound will facilitate further research into its role in NMD and stress response pathways.
- Targeting hSMG-1 offers a potential strategy to overcome tumor growth and chemotherapy resistance.
