作者: Bin Li , Darren Orton , Leif R. Neitzel , Luisana Astudillo , Chen Shen
DOI: 10.1126/SCISIGNAL.AAK9916
关键词:
摘要: Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no inhibitor is currently approved for use clinic largely due to small number druggable signaling components pathway and substantial toxicity normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), a potent signaling. However, its poor bioavailability limited ability test first-in-class vivo. characterized novel small-molecule CK1α activator called SSTC3, has better pharmacokinetic properties than found it inhibited CRC xenografts mice. SSTC3 also attenuated patient-derived metastatic xenograft, few therapies exist. exhibited minimal compared other classes inhibitors. Consistent with observation, we showed abundance target, CK1α, was decreased WNT-driven tumors relative tissue, knocking down increased cellular sensitivity SSTC3. Thus, propose distinct provides an enhanced therapeutic index pharmacological activators target tumors.