Casein kinase1α activators, a precision weapon for CRC

The evolutionarily conserved Wnt signaling pathway provides temporal and spatial cues during early embryonic development and during homeostatic function of numerous adult tissues [1]. Wnt signaling also drives the onset and progress of a broad array of human cancers, including nearly all nonhereditary colorectal cancers (CRCs) [1]. Despite the importance of this pathway in cancer, no Wnt inhibitors are currently clinically approved. Wnt ligands are palmitoylated in the endoplasmic reticulum by the membrane bound O-acyltransferase, Porcupine, and palmitoylation of Wnt ligands is necessary for secretion of the active protein as well as high affinity binding to the Frizzled receptor [1]. To date, Porcupine inhibitors represent a particularly promising class of Wnt inhibitors that have proven effective in many Wnt ligand-driven preclinical cancer models. Porcupine inhibitors are currently being evaluated in clinical trials. Porcupine inhibitors, however, are unlikely to be useful for targeting CRC, the vast majority of which harbor activating mutations downstream of Wnt ligands. The critical event in the Wnt pathway involves posttranslational regulation of the transcriptional co-activator β-Catenin. In the absence of Wnt signaling, β-Catenin is maintained at low levels in the cytoplasm via its association with a “destruction complex,” which consists of Glycogen Synthase Kinase 3 (GSK3), Casein Kinase 1α (CK1α), Adenomatous Polyposis Coli (APC), and the scaffold protein Axin. Within this complex, β-Catenin is phosphorylated, thereby targeting it for ubiquitin-mediated degradation [1]. The rate-limiting component in the destruction complex is Axin, and its steady-state protein levels are regulated by the poly-adenosine diphosphateribose polymerase, Tankyrase. Small-molecule Tankyrase inhibitors, which exhibited considerable efficacy in APC mutant CRC cell lines, have emerged as a promising class of novel therapeutics. However, Tankyrase inhibitors exhibit overt on-target gastrointestinal (GI) toxicity in mouse CRC models due to effects on the Wnt-dependent intestinal stem cells that maintain normal GI homeostasis [2]. Such a limited therapeutic index (at least in preclinical animal models) may ultimately limit progression of Tankyrases inhibitors into the clinic and their utility for CRC patients. We initially described the identification of a mechanistically distinct Wnt inhibitor, pyrvinium, using a high-throughput small-molecule screen [3]. This first-inclass small-molecule Wnt inhibitor bound to and activated the protein kinase CK1α. Given the role CK1α plays as a negative regulator of Wnt signaling, this pharmacological activation of CK1α resulted in the reduced viability of CRC cell lines in vitro. Interestingly, pyrvinium was previously approved by the FDA and used successfully and safely for many decades in the clinic as an antipinworm medication. The bioavailability of pyrvinium was limited to the GI tract upon oral administration, a positive attribute for an anthelmintic drug, but one that limited its repurposing as a Wnt inhibitor for CRC patients. In a recent study, we described the development and characterization of a second-generation pharmacological activator of CK1α, SSTC3, which exhibited significantly improved bioavailability compared to pyrvinium [4]. Similar to pyrvinium, SSTC3 attenuated CRC growth in vitro and prolonged the survival of a mouse CRC tumor mouse model. Taking advantage of the improved pharmacokinetics of SSTC3, we showed for the first time the efficacy of CK1α activators in attenuating the growth of CRC in vivo using both cell lines and patientderived CRC xenografts (including a lung metastatic cancer harboring a KRas mutation that was derived from a patient). We found that SSTC3 exhibited greater efficacy than a Tankyrase inhibitor in reducing CRC growth and demonstrated significantly less on-target GI toxicity in mice. We showed that this increased therapeutic index of SSTC3 was due to the differential abundance of CK1α, the direct target of SSTC3, in normal GI tissue relative to that in tumor tissue (Figure 1). We further showed that reduced levels of CK1α correlated with decreased survival of CRC patients [4]. These findings validate CK1α as a bona fide, Editorial