MEDI 351 |
| Hsp90 inhibitors in advanced development for cancer can broadly be classified into two groups: semi-synthetic derivatives of naturally occurring ansamycins and small molecules, such as mimetics of adenosine and non-purine based resorcinol compounds. Semi-synthetic ansamycins such as 17-DMAG and 17-AAG, contain a common quinone ‘toxicophore'. Through genetic engineering of the macbecin biosynthetic pathway we have now prepared a series of derivatives that lack the undesired quinone moiety. The most potent compound of this series has a binding affinity (Kd) of 3 nM to Hsp90, and is much better tolerated in vivo than 17-AAG (MTTD ≥ 250 mg/kg vs ~50 mg/kg i.p. in mice). It showed equivalent in vivo tumor growth inhibition in xenograft models at ≤ 1/3 MTTD to that of 17-AAG at MTTD. The improved therapeutic index coupled with its potent inhibition of Hsp90 makes the compound potentially the ‘best-in-class' Hsp90 inhibitor described to-date. |
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |