The KRAS on
cogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a trans
cript en
coding the serine/threonine kinase STK33 was sele
ctively toxi
c to KRAS-dependent
can
cer
cell lines, suggesting that small-mole
cule inhibitors of STK33 might sele
ctively target KRAS-dependent
can
cers. To test this hypothesis, we initiated a high-throughput s
creen using
compounds in the Mole
cular Libraries Small Mole
cule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was optimized. Extensive SAR studies were performed and led to the
chemi
cal probe ML281 that showed low nanomolar inhibition of purified re
combinant STK33 and a distin
ct sele
ctivity profile as
compared to other STK33 inhibitors that were reported in the
course of these studies. Even at the highest
con
centration tested (10 渭M), ML281 had no effe
ct on the viability of KRAS-dependent
can
cer
cells. These results are
consistent with other re
cent reports using small-mole
cule STK33 inhibitors. Small mole
cules having different
chemi
cal stru
ctures and kinase-sele
ctivity profiles are needed to fully understand the role of STK33 in KRAS-dependent
can
cers. In this regard, ML281 is a valuable addition to small-mole
cule probes of STK33.
Keywords:
cs.org/action/doSearch?action=search&searchText=STK33+inhibitor&qsSearchArea=searchText">STK33 inhibitor; cs.org/action/doSearch?action=search&searchText=KRAS+synthetic+lethality&qsSearchArea=searchText">KRAS synthetic lethality; cs.org/action/doSearch?action=search&searchText=MLPCN+probe&qsSearchArea=searchText">MLPCN probe