MEDI 463 |
| We are developing water-soluble, ansamycin polyketides as potent Hsp90 inhibitors. Macbecin (1) has been characterized as an alternative lead to geldanamycin. (1) has a 5-fold higher affinity than geldanamycin for binding to Hsp90. Macbecin lacks a chemical ‘handle' for prodrug formation, so our strategy centered on the reduction of the quinone to a hydroquinone and then connection to ionisable groups to improve water solubility through either an ester or carbamate linkage. (2), from this chemical series, has aqueous solubility of >20 mM. It is stable at pH <6.5 but converts to macbecin under physiological conditions, e.g. in plasma with a t1/2 of 45-50 min. The conversion is not enzyme-dependent and therefore devoid of potential issues from metabolic polymorphism. (2) showed a significantly improved MTTD over (1). When given at 60 mg/kg to mice bearing DU145 prostate tumor xenograft, (2) produced potent inhibition in tumor growth.
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General Oral Session
1:30 PM-4:50 PM, Thursday, August 23, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |
