The KRAS oncogene is found in up to 30% of all hu
man tu
mors. In 2009, RNAi experi
ments 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 s
mall-
molecule inhibitors of STK33
might selectively target KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screen using co
mpounds in the Molecular Libraries S
mall Molecule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was opti
mized. Extensive SAR studies were perfor
med and led to the che
mical probe ML281 that showed low nano
molar inhibition of purified reco
mbinant STK33 and a distinct selectivity profile as co
mpared to other STK33 inhibitors that were reported in the course of these studies. Even at the highest concentration tested (10 渭M), ML281 had no effect on the viability of KRAS-dependent cancer cells. These results are consistent with other recent reports using s
mall-
molecule STK33 inhibitors. S
mall
molecules having different che
mical 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 s
mall-
molecule probes of STK33.
Keywords:
STK33 inhibitor; KRAS synthetic lethality; MLPCN probe