Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2 and is involved in G 2 checkpoint signaling. Because p53 is a key regulator in the G 1 checkpoint, p53-deficient tumors rely only on the G 2 checkpoint after DNA damage. Hence, such tumors are selectively sensitized to DNA-damaging agents by Wee1 inhibition. Here, we report the discovery of a potent and selective smallmolecule inhibitor of Wee1 kinase, MK-1775. This compound inhibits phosphorylation of CDC2 at Tyr15 (CDC2Y15), a direct substrate of Wee1 kinase in cells. MK-1775 abrogates G 2 DNA damage checkpoint, leading to apoptosis in combination with DNA-damaging chemotherapeutic agents such as gemcitabine, carboplatin, and cisplatin selectively in p53-deficient cells. In vivo, MK-1775 potentiates tumor growth inhibition by these agents, and cotreatment does not significantly increase toxicity. The enhancement of antitumor effect by MK-1775 was well correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles. Our data indicate that Wee1 inhibition provides a new approach for treatment of multiple human malignancies.

The thermally induced insulator-metal transition ͑IMT͒ has been investigated for single crystals of undoped and lightly doped LaCoO 3 by measurements of the optical-conductivity spectra, the resistivity, and the Hall coefficient up to 800 K. The IMT around 500 K, where the spin-state transition from the nonmagnetic (S ϭ0) ground state to the intermediate-spin (Sϭ1) state is nearly completed, is characterized by a large energy-scale change of the electronic structure as well as by a steep increase of carrier number up to a typical metallic value due to closing of the charge gap. These behaviors are strikingly parallel to those characteristic of the Mott transition. ͓S0163-1829͑98͒50628-5͔PRB 58

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The first order phase transition of a water cluster confined in a dynamic single-walled carbon nanotube is investigated using a classical molecular dynamics (MD) method. The formation of ice-nanotube is monitored through the structure factor and potential energies. The transition temperature and its diameter dependence obtained by the simulations agree well with those of previously reported experiments. The transition temperature of the ice-nanotube was shown to take a maximum value of around room temperature with the number of the ring members n=5. Potential energy contribution to the phase change is generally dominated by that of the intrinsic water-water interaction, while that of water-carbon interaction plays a significant role on determining the dependence of transition temperature on the nanotube diameter.