Development and Characterization of a Wee1 Kinase Degrader

ABSTRACT: The G1/S cell-cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells particularly reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Inhibiting regulators of the G2/M checkpoint can therefore drive cancer cells into premature mitosis, ultimately causing cell death by mitotic catastrophe. One such regulator is Wee1, a nuclear tyrosine kinase that delays mitotic entry by phosphorylating CDK1 at Tyr15. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose- limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we designed small molecule degraders of Wee1 by conjugating AZD1775 to the cereblon (CRBN)- binding ligand, pomalidomide, as informed by molecular docking. The resulting lead compound, ZNL- 02-096, degrades Wee1 while sparing PLK1, induces G2/M phase accumulation at up to 10-fold lower concentrations than AZD1775, and potently synergizes with Olaparib in ovarian cancer cell lines. We demonstrate that ZNL-02-096 has CRBN-dependent pharmacology that is distinct from the conventional catalytic inhibitor, AZD1775, which justifies further evaluation of selective Wee1 degraders.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer  

LAB HEAD: Eric Fischer

PROVIDER: PXD015513 | Pride | 2019-11-18

REPOSITORIES: pride