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A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells
Michel Weïwer1, James Spoonamore, Jingqiang Wei
1Broad Institute of Harvard and MIT , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
Abstract:
The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screen using compounds in the Molecular Libraries Small Molecule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was optimized. Extensive SAR studies were performed and led to the chemical probe ML281 that showed low nanomolar inhibition of purified recombinant STK33 and a distinct selectivity profile as compared to other STK33 inhibitors that were reported in the course of these studies. Even at the highest concentration tested (10 μM), ML281 had no effect on the viability of KRAS-dependent cancer cells. These results are consistent with other recent reports using small-molecule STK33 inhibitors. Small molecules having different chemical structures and kinase-selectivity profiles are needed to fully understand the role of STK33 in KRAS-dependent cancers. In this regard, ML281 is a valuable addition to small-molecule probes of STK33.
Insights
Researchers investigated serine/threonine kinase 33 (STK33) as a potential target for KRAS-dependent cancers. They developed a chemical probe, ML281, which inhibited STK33 but did not affect cancer cell viability, suggesting STK33 is not a viable target for these cancers.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- The KRAS oncogene is implicated in up to 30% of human cancers.
- RNAi experiments indicated that serine/threonine kinase 33 (STK33) is selectively toxic to KRAS-dependent cancer cells.
- This suggested that STK33 inhibitors could be a targeted therapy for KRAS-dependent cancers.
Purpose of the Study:
- To identify and develop small-molecule inhibitors of STK33.
- To evaluate the efficacy of STK33 inhibitors in targeting KRAS-dependent cancers.
Main Methods:
- High-throughput screening of compounds from the Molecular Libraries Small Molecule Repository (MLSMR).
- Optimization of a quinoxalinone derivative through structure-activity relationship (SAR) studies.
- Characterization of the chemical probe ML281 for STK33 inhibition and selectivity.
Main Results:
- A chemical probe, ML281, was developed, exhibiting low nanomolar inhibition of purified recombinant STK33.
- ML281 demonstrated a distinct selectivity profile compared to other reported STK33 inhibitors.
- ML281 did not affect the viability of KRAS-dependent cancer cells, even at high concentrations (10 μM).
Conclusions:
- The findings suggest that STK33 may not be a viable therapeutic target for KRAS-dependent cancers.
- ML281 serves as a valuable chemical probe for further research into STK33's role in cancer.
- Additional small molecules with diverse chemical structures and kinase selectivity are needed to fully elucidate STK33's function in KRAS-dependent cancers.
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