FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe.

WEE1 kinase phosphorylates CDK1 and CDK2 to regulate origin firing and mitotic entry. Inhibition of WEE1 has become an attractive target for cancer therapy due to the simultaneous induction of replication stress and inhibition of the G2/M checkpoint. WEE1 inhibition in cancer cells with high levels of replication stress results in induction of replication catastrophe and mitotic catastrophe. To increase potential as a single agent chemotherapeutic, a better understanding of genetic alterations that impact cellular responses to WEE1 inhibition is warranted. Here, we investigate the impact of loss of the helicase, FBH1, on the cellular response to WEE1 inhibition. FBH1-deficient cells have a reduction in ssDNA and double strand break signaling indicating FBH1 is required for induction of replication stress response in cells treated with WEE1 inhibitors. Despite the defect in the replication stress response, FBH1-deficiency sensitizes cells to WEE1 inhibition by increasing mitotic catastrophe. We propose loss of FBH1 is resulting in replication-associated damage that requires the WEE1-dependent G2 checkpoint for repair.

Design of the elusive proteinaceous oxygen donor copper site suggests a promising future for copper for MRI contrast agents.

We report the preparation and spectroscopic characterization of a highly elusive copper site bound exclusively to oxygen donor atoms within a protein scaffold. Despite copper generally being considered unsuitable for use in MRI contrast agents, which in the clinic are largely Gd(III) based, the designed copper coiled coil displays relaxivity values equal to, or superior than, those of the Gd(III) analog at clinical field strengths. The creation of this new-to-biology proteinaceous CuOx-binding site demonstrates the power of the de novo peptide design approach to access chemistry for abiological applications, such as for the development of MRI contrast agents.

FBH1 deficiency sensitizes cells to WEE1 inhibition by promoting mitotic catastrophe.

WEE1 kinase phosphorylates CDK1 and CDK2 to regulate origin firing and mitotic entry. Inhibition of WEE1 has become an attractive target for cancer therapy due to the simultaneous induction of replication stress and inhibition of the G2/M checkpoint. WEE1 inhibition in cancer cells with high levels of replication stress results in induction of replication catastrophe and mitotic catastrophe. To increase potential as a single agent chemotherapeutic, a better understanding of genetic alterations that impact cellular responses to WEE1 inhibition is warranted. Here, we investigate the impact of loss of the helicase, FBH1, on the cellular response to WEE1 inhibition. FBH1-deficient cells have a reduction in ssDNA and double strand break signaling indicating FBH1 is required for induction of replication stress response in cells treated with WEE1 inhibitors. Despite the defect in the replication stress response, FBH1-deficiency sensitizes cells to WEE1 inhibition by increasing mitotic catastrophe. We propose loss of FBH1 is resulting in replication-associated damage that requires the WEE1-dependent G2 checkpoint for repair.

'Two is better than one'--probes for dual-modality molecular imaging.

Molecular or personalised medicine is the future of patient management and healthcare, and molecular imaging plays a key role towards this goal. However, amongst molecular imaging techniques, no single modality is perfect and sufficient to gain all the necessary information. For instance, optical fluorescence imaging is difficult to quantify--especially in tissue more than a few millimetres in depth within a subject; magnetic resonance imaging (MRI) has superb resolution but low sensitivity and positron emission tomography (PET) has very high sensitivity but poor resolution. The combination of multiple molecular imaging techniques can therefore offer synergistic advantages over any modality alone. However, the problem cannot be solved by simply adding two different classes of imaging probes together, unless they happen to have identical pharmacodynamic properties. Therefore, multi-modal contrast agents or imaging probes have been developed to solve this problem. Despite the great wealth of information that such probes can provide, their development is far from trivial and represents an important challenge to synthetic chemists. In this feature article, we provide an overview of recent findings in the synthesis, evaluation and application of dual-modality molecular imaging probes.