Chemical genomics

Gene expression-based high-throughput screening (GE-HTS) and application to leukemia differentiation. Stegmaier, K. et al. Nature Genet. 36, 257–263 (2004).

Chemical genomics, which involves generating large collections of small molecules and using them to modulate cellular states, is emerging as a powerful tool for probing biological function. However, the speed at which small-molecule probes that have a particular cellular effect can be found is often limited by lack of knowledge of the target proteins involved. In such cases, small molecules are typically screened for an effect using low-throughput assays; for example, assays based on cell morphology. The authors describe a general, high-throughput approach for addressing this issue in which a gene-expression signature is used as a surrogate for cellular states, the utility of which they demonstrate by identifying several compounds from a 1,739-member library that induce the differentiation of acute myeloid leukaemia cells.

Anticancer drugs

Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Mitsiades, C. S. et al. Cancer Cell 26 Feb 2004 (doi:10.1016/S1535610804000509).

In vivo antitumor activity of NVP-AEW541 — a novel, potent, and selective inhibitor of the IGF-IR kinase. García-Echeverría, C. et al. Cancer Cell 26 Feb 2004 (doi:10.1016/S153561080 4000510).

Insulin-like growth factors and their receptor, IGF-1R, have been linked to a wide range of cancers, but this pathway has not previously been viewed as a major therapeutic target, in part owing to the lack of clinically applicable small-molecule inhibitors of IGF-1R function. Using selective small-molecule inhibitors of the IGF-1R kinase, these two papers provide in vivo proof of concept for the use of such inhibitors as primary antitumour therapy or in combination with cytotoxic chemotherapy.

Drug delivery

Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Fainaro-Satchi, R. et al. Nature Med. 10, 255–261 (2004).

The small molecule TNP-470 inhibits tumour angiogenesis — the growth of new blood vessels necessary for tumour progression — and has shown activity in cancer patients. However, at the higher doses necessary for tumour regression, many patients experienced neurotoxicity. This paper shows that conjugating TNP-470 to a biocompatible copolymer prevents it crossing the blood–brain barrier, and also leads to its selective accumulation in tumour vessels, thereby minimizing toxicity.