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  • Undergraduate Poster Abstracts
  • SAT-1047 SIGNALLING EFFECTS FROM THE INHIBITION OF CNKSR1 PH-DOMAIN IN CANCER CELL LINES

    • Assael Madrigal ;

    SAT-1047

    SIGNALLING EFFECTS FROM THE INHIBITION OF CNKSR1 PH-DOMAIN IN CANCER CELL LINES

    Assael Madrigal, Gallen Triana-Blatzer, Lynn Kirkpatrick.

    PHusis Therapeutics, San Diego, CA.

    Kirsten rat sarcoma viral oncogene homolog (KRAS) is found to be mutated in 25% of cancers and is central to the development of cancer. Mutant-KRAS (mut-KRAS) is also involved in the resistance to many cancer therapies. The connector enhancer of kinase suppressor of RAS1 (CNKSR1) is a protein found to be associated with and is critical for the activity of mut-KRAS but not wild-type KRAS. Thus CNKSR1 is an important target for cancer therapy. PHusis Therapeutics has developed small molecule inhibitors with high affinity for CNKSR1 using its in silico modeling system. Our goal is to optimize these compounds through surface plasmon resonance spectroscopy, synthetic chemistry, and drug design. We evaluate our leads in vitro for the effects of KRAS signaling by western blot and immunoprecipitation. This project involved evaluating target inhibition by novel potent inhibitors of mut-KRAS cell line growth that showed binding to the isolated CNKSR1 PH-domain. Three compounds were evaluated for direct target inhibition in both mut-KRAS and wt-KRAS cell lines in culture for the active form of RAS and its downstream effectors. Cells were treated with varying concentrations of the compounds for 24 hr and assessed for target inhibition. Data will be presented to show the cellular effects on growth and target inhibition by the three novel CNKSR1 inhibitors. The conclusions from this work are that the inhibition of CNKSR1 by small molecules leads to inhibition of the active form of RAS and to the inhibition of cancer cell growth that is driven by mut-KRAS.