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Published on: March 12, 2019
Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent
Bin Li1, Darren Orton2, Leif R Neitzel3
1Molecular Oncology Program, Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Abstract:
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 1α (CK1α), 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 CK1α 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, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.
Insights
A new drug, SSTC3, activates casein kinase 1 alpha (CK1α) to inhibit WNT signaling in colorectal cancer (CRC) with minimal toxicity. This discovery offers a promising therapeutic strategy for WNT-driven tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Constitutive WNT signaling drives numerous human cancers, particularly colorectal cancer (CRC).
- Current WNT inhibitors face challenges due to limited druggable targets and significant gastrointestinal toxicity.
- Pyrvinium, a casein kinase 1 alpha (CK1α) activator, shows WNT inhibition potential but suffers from poor bioavailability.
Purpose of the Study:
- To characterize a novel small-molecule CK1α activator, SSTC3, with improved pharmacokinetic properties.
- To evaluate SSTC3's efficacy and safety as a WNT inhibitor in preclinical models of colorectal cancer.
- To explore the role of CK1α abundance in determining therapeutic efficacy and toxicity.
Main Methods:
- Pharmacokinetic profiling of SSTC3.
- Assessment of SSTC3's anti-tumor activity in colorectal cancer xenografts (mouse models).
- Evaluation of gastrointestinal toxicity and analysis of CK1α expression in tumor and normal tissues.
Main Results:
- SSTC3 demonstrated potent inhibition of WNT signaling and suppressed the growth of CRC xenografts.
- SSTC3 effectively reduced the growth of a patient-derived metastatic CRC xenograft.
- SSTC3 exhibited minimal gastrointestinal toxicity compared to other WNT inhibitors, correlating with lower CK1α abundance in tumors versus normal tissues.
Conclusions:
- SSTC3 is a promising first-in-class WNT inhibitor with improved bioavailability and a favorable safety profile.
- Differential CK1α abundance between WNT-driven tumors and normal tissues may provide a therapeutic window for CK1α activators.
- SSTC3 represents a potential novel therapeutic strategy for colorectal cancer and other WNT-driven malignancies.
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