Discovery and Synthesis of Selective Casein Kinase 1δ Degraders for Suppressing Oncogenic NRAS-Mutant Melanoma.

Activating NRAS mutations occur in approximately 20% of melanomas but remain largely undruggable due to the lack of effective targeted therapies. We previously identified casein kinase 1δ (CK1δ) as a critical upstream regulator that stabilizes oncogenic NRAS mutants. However, no selective CK1δ inhibitors have advanced to clinical evaluation. Here, we report the discovery of 8u, a selective CK1δ degrader derived from PF-670462. Compound 8u potently degrades CK1δ in NRASQ61R melanoma cells (DC50 = 1.25 μM, Dmax = 74%) via the ubiquitin-proteasome system, sparing against the closely related isoform CK1α and CK1ε. CK1δ degradation induced by 8u leads to destabilization of NRASQ61R and attenuation of downstream signaling pathways. Furthermore, 8u elicited significant tumor regression (TGI = 58.9%) in an NRASQ61R xenograft model in vivo at 30 mg/kg. The studies establish targeted degradation of CK1δ as a promising therapeutic strategy for NRAS-mutant melanoma.