Aneuploidy and chromosomal instability are major characteristics of human cancer. These abnormalities can result from defects in the spindle assembly checkpoint (SAC), which is a surveillance mechanism for accurate chromosome segregation through restraint of the activity of the anaphase-promoting complex/cyclosome (APC/C). Here, we show that a CUE-domain-containing protein, CUEDC2, is a cell-cycle regulator that promotes spindle checkpoint inactivation and releases APC/C from checkpoint inhibition. CUEDC2 is phosphorylated by Cdk1 during mitosis. Depletion of CUEDC2 causes a checkpoint-dependent delay of the metaphase-anaphase transition. Phosphorylated CUEDC2 binds to Cdc20, an activator of APC/C, and promotes the release of Mad2 from APC/C-Cdc20 and subsequent APC/C activation. CUEDC2 overexpression causes earlier activation of APC/C, leading to chromosome missegregation and aneuploidy. Interestingly, CUEDC2 is highly expressed in many types of tumours. These results suggest that CUEDC2 is a key regulator of mitosis progression, and that CUEDC2 dysregulation might contribute to tumour development by causing chromosomal instability.
Fibroblast
growth factor receptors (FGFRs) have become promising
therapeutic targets in various types of cancers. In fact, several
selective irreversible inhibitors capable of covalently reacting with
the conserved cysteine of FGFRs are currently being evaluated in clinical
trials. In this article, we optimized and discovered a novel lead
compound 36 with remarkable inhibitory effects against
FGFR (1–3), which is a derivative of 2H-pyrazolo[3,4-d]pyrimidine.
The irreversible binding to FGFRs was characterized by LC–MS.
This compound has been shown to exhibit significant anti-proliferation
effects against NCI-H1581 and SNU-16 cancer cell lines both in vitro and in vivo. Compound 36 has also demonstrated a low toxicity profile and adequate pharmacokinetic
properties and is currently under validation as a potential drug candidate.
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