Anticancer Drugs

Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Cho, H.-S. et al. Nature 421, 756–760 (2003)

Overexpression of the receptor tyrosine kinase HER2 is found in 20–30% of breast cancer cases, and trastuzumab (Herceptin; Genentech) — a monoclonal antibody against HER2 — has been approved for the treatment of such patients. The authors report the crystal structure of human HER2 complexed with the Herceptin antigen-binding fragment, which reveals a region of the receptor that could be a promising target for the development of drugs with improved therapeutic properties.

Computational Chemistry

Absorption classification of oral drugs based on molecular surface properties. Bergström, C. A. S. et al. J. Med. Chem. 46, 558–570 (2003)

The recognition that poor pharmacokinetic properties have been an important cause of costly late-stage failures in drug development has led to increasing interest in computational approaches for the prediction of such properties as early as possible in the drug discovery process. The authors describe computational models that can rapidly predict the solubility and permeability of structurally diverse molecules with high accuracy from calculated molecular surface properties alone.

Stroke

Activated protein C blocks p53-mediated apoptosis in ischemic human brain and is neuroprotective. Cheng, T. et al. Nature Med. 3 Feb 2003 (doi: 10.1038/nm826)

Activated protein C (APC) is a systemic anticoagulant and anti-inflammatory factor, a recombinant form of which has recently been approved for the treatment of severe sepsis. Cheng et al. show that APC can protect the brain from ischaemic injury by directly inhibiting apoptosis in brain cells, indicating that APC could be valuable in the treatment of stroke and other neurodegenerative diseases.

Anticancer Drugs

Selective killing of cancer cells by β-lapachone: direct checkpoint activation. Li, Y. et al. Proc. Natl Acad. Sci. USA 100, 2674–2678 (2003)

The cell-proliferation cycle has inbuilt checkpoints at which apoptosis is activated if DNA damage is irreparable, thereby safeguarding genomic integrity. Many traditional anticancer drugs kill cancer cells by causing nonselective DNA damage, leading to activation of checkpoint-mediated apoptosis, but are therefore also toxic to normal cells. Li et al. report that β-lapachone can selectively induce apoptosis in cancer cells through a regulatory pathway that links checkpoint activation with apoptosis, indicating that direct checkpoint activation could be a novel anticancer strategy.