GW572016 (Lapatinib) is a dual EGFR/ErbB-2 kinase inhibitor in clinical development. Wood et al. determined the structure of EGFR bound to GW572016 and found it is significantly different from EGFR bound to a related inhibitor, Tarceva. GW572016 was found to have a significantly slower off-rate from purified EGFR than Tarceva and the slow off-rate correlates with a prolonged suppression of receptor activity in tumor cells. The GW572016/EGFR structure provides potential explanations for the compound's slow-off rate and ability to inhibit ErbB-2. The cover image shows the structure of the ATP binding pocket of EGFR bound to GW572016. The compound protrudes deep into a back pocket that was not present in structures of apo-EGFR or EGFR bound to Tarceva. (The authors wish to acknowledge Aaron Miller for production of this image of the GW572016/EGFR structure.) For details, see the article by Wood et al. on page 6652 of this issue.

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