CK1 alpha degrader GLB-001

An orally bioavailable molecular glue degrader of casein kinase 1 alpha (CK1alpha; CK1a), with potential antineoplastic activity. Upon oral administration, CK1a degrader GLB-001 targets and binds to CK1a, and to E3 ubiquitin ligase, thereby creating a ternary complex. This induces E3 ligase ubiquitination and proteasome-mediated degradation of CK1a, and inhibits the activity of CK1a. This prevents the enhanced binding of murine double minute X (MDMX) to p53, reduces the formation of CK1a and MDM2 complex, and prevents the interaction of MDM2 with p53. This prevents the inhibition of p53 and increases p53 activity. This induces p53-mediated cell cycle arrest, thereby inhibiting tumor cell proliferation. CK1a, a serine/threonine kinase and a leukemic stem cell target, acts as a tumor suppressor in several cancers through the negative regulation of Wnt/beta-catenin signaling and p53. It negatively regulates p53 by phosphorylating MDMX, thus enhancing binding of MDMX to p53, as well as by forming a complex with MDM2.