ABSTRACT
Wee1 is a kinase that regulates cell cycle arrest in response to DNA damage. Wee1 inhibition is a potential strategy to suppress the growth of tumors with defective p53 or DNA repair pathways. However, the development of Wee1 inhibitors faces some challenges. AZD1775, the first-in-class Wee1 inhibitor, has poor kinase selectivity and dose-limiting toxicity. Here, we report the discovery of 12h, a highly selective and potent Wee1 inhibitor with a favorable pharmacokinetic profile. 12h showed strong antiproliferative effects against Lovo cells, a colorectal cancer cell line, both in vitro and in vivo. Moreover, 12h showed a clean kinase profile and effectively induced cell apoptosis. Our results suggest that 12h is a promising drug candidate for further development as a novel anticancer agent.
Subject(s)
Antineoplastic Agents , Cell Cycle Proteins , Cell Proliferation , Drug Design , Protein Kinase Inhibitors , Protein-Tyrosine Kinases , Humans , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/chemistry , Animals , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/chemistry , Cell Proliferation/drug effects , Apoptosis/drug effects , Mice , Structure-Activity Relationship , Mice, NudeABSTRACT
The practical application of the metallic lithium anode is suppressed by the highly unstable interface between electrolytes and lithium metal during the process of lithium plating/stripping. A perfect solid electrolyte interphase (SEI) can inhibit detrimental parasitic reactions, thereby improving the cycling performance of the metallic lithium anode. In this work, a high-purity solid lithium difluorobis(oxalato) phosphate (LiDFOP) is synthesized and an outstanding organic-inorganic hybrid SEI is obtained in an ether-based electrolyte for the first time induced by LiDFOP. The preferential reduction of LiDFOP can form an SEI rich in LiF and LixPOyFz species, thereby improving the conductivity and stability of the SEI. In addition, cationic-induced ring-opening polymerization between LiDFOP and 1,3-dioxolane endows the SEI with excellent adaptability to the reiterative volume change of the metallic lithium anode. Therefore, the Li/Cu battery maintains a high coulombic efficiency of 98.37% at a current density of 2 mA/cm2 for 200 cycles, and the Li/Li symmetrical battery shows stable voltage hysteresis over 1000 h even under the condition of 5 mA/cm2. The Li/S battery fabricated employing the electrolyte with LiDFOP shows significant improvement of cycling performance as well. These results manifest that the formation of an organic-inorganic hybrid SEI from LiDFOP can be employed as a new strategy to overcome the problem from the unstable SEI in metallic lithium batteries.