The National Cancer Institute estimates that there will be 1,735,350 new cases of cancer in 2018 in the US. Activating mutations of a key enzyme in humans, called KRAS, are known to occur in about 20% of all human cancers. Combining these two statistics, we estimate that about 350,000 US residents will be affected by one or another form of KRAS-related cancers per year. Currently, there are no drugs that can directly act on mutated KRAS to stop its cancer-causing activities. As a result, KRAS-related cancers, which include some of the deadliest, such as pancreatic cancer, remain untreatable. Clearly, anti-KRAS medications would save millions of lives. Supported by a previous CPRIT grant, we...

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The National Cancer Institute estimates that there will be 1,735,350 new cases of cancer in 2018 in the US. Activating mutations of a key enzyme in humans, called KRAS, are known to occur in about 20% of all human cancers. Combining these two statistics, we estimate that about 350,000 US residents will be affected by one or another form of KRAS-related cancers per year. Currently, there are no drugs that can directly act on mutated KRAS to stop its cancer-causing activities. As a result, KRAS-related cancers, which include some of the deadliest, such as pancreatic cancer, remain untreatable. Clearly, anti-KRAS medications would save millions of lives. Supported by a previous CPRIT grant, we have been working toward developing an effective KRAS inhibitor by combining physics-based computations, high-end biophysical, biochemical and biological experiments. This resulted in 800 candidate KRAS inhibitors. We tested 110 of these compounds for their ability to directly interact with mutant KRAS and mitigate its abnormal functions. 11 exhibited the desired inhibitory activities in cells. This represents an unprecedented success rate of 10%. We attribute this success to our unique methodological approach that takes advantage of our detailed understanding of the dynamic nature of KRAS, which is critical for its normal and abnormal functions. We then conducted very detailed validation studies on four of the most promising compounds, and found that three of these represent first-in-class KRAS inhibitors with unique mechanisms of inhibition. In this application, we propose to (i) advance these compounds to eventual clinical use through rational optimization for improved physiological activities, (ii) conduct additional biochemical, structural, biophysical and cell biological characterizations of the remaining seven compounds in search of additional drug leads, and (iii) lay the groundwork for future preclinical studies in animal models.

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