v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most mutated oncogene, and KRAS mutations have been found in up to 20% of all human tumors. In 2009, Serine/threonine-protein kinase 33 (STK33) was identified as a synthetic lethal gene in KRAS-dependent cell lines through Ribonucleic Acid Interference (RNAi) experiments. Hence STK33 could potentially be a critical target in KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screening campaign to look for STK33 inhibitors. The Molecular Libraries Small Molecule Repository (MLSMR) was screened, and two promising scaffolds were identified: one based on a thiazolone and the other one based on a quinoxalinone. Extensive SAR was performed on both scaffolds, and two new inhibitors of STK33 were discovered. These compounds (CID 5765514/ML280 and CID 53377448/ML281) will serve to test the relevance of STK33 as a viable target for the selective killing of KRAS-dependent cells. While our medicinal chemistry efforts were ongoing, a research group at Amgen described RNAi experiments conducted in a large panel of KRAS mutant and KRAS wild-type cell lines. This study concluded that STK33 is not required for the survival of KRAS mutant cell lines. In addition, the Amgen team developed small-molecule inhibitors of STK33 and demonstrated that they had no effect in selectively killing KRAS mutant cell lines. Because of the controversy on the legitimacy of STK33 as a target for the selective killing of KRAS mutant cell lines, we pursued our medicinal chemistry efforts to provide new classes of STK33 inhibitors to the cancer research community to test this hypothesis and to help elucidate the role of STK33 in different cancer cell lines. We find that our probes do not lead to KRAS dependent cell death.