Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1 alpha (CK1 alpha), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1 alpha activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1 alpha, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1 alpha increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1 alpha abundance provides an enhanced therapeutic index for pharmacological CK1 alpha activators to target WNT-driven tumors.