Wee1 Degrader BMS-986463

**Semantic type:** Pharmacologic Substance

**Definition:** A modulator of the E3 ubiquitin ligase complex containing cereblon (CRL4-CRBN E3 ubiquitin ligase) and targeted degrader of human tyrosine kinase Wee1 (Wee1-like protein kinase; Wee1A kinase; WEE1hu), with potential antineoplastic activity. Upon administration, Wee1 degrader BMS-986463 specifically targets and binds to cereblon (CRBN), a component of the CRL4-CRBN E3 ubiquitin ligase complex. This catalyzes ubiquitination and proteasome-mediated degradation of Wee1. Degradation of Wee1 inhibits cyclin-dependent kinase 1 (CDK1) and 2 (CDK2) phosphorylation, promotes both premature mitosis and a prolonged mitotic arrest, which results in the accumulation of unrepaired DNA damage. This leads to apoptosis in susceptible tumor cells, such as p53-deficient or mutated human cancers that lack the G1 checkpoint, and G1/S-specific cyclin-E1 (CCNE1)-overexpressing tumor cells that coordinate with CDK2 to facilitate G1/S progression of cell cycle. Overexpression of Wee1 occurs in several cancer types and high expression of Wee1 is associated with poor outcomes. Wee1 phosphorylates CDK1 and CDK2, which blocks cell cycle progression from S/G2 to M phase, and G1 to S phase; it negatively regulates the G2 checkpoint by disallowing entry into mitosis in response to DNA damage.

**Synonyms:** - BMS 986463 - BMS-986463 - BMS986463 - CELMoD BMS-986463 - Cereblon E3 Ligase Modulating Drug BMS-986463