Tute, the on-screen in vitro against 60 tumor cell lines, reached GM growth inhibition of 50% at 13 nm in cell lines and is very sensitive Accessible points to an average of 180 nM.29 The crystal structure Brivanib BMS-540215 of GM Co with yeast Hsp90 that it binds tightly to the ATP pocket of the N-terminal domain ne with Kd 1.2 M.30 The benzoquinone ring is located near the entrance of the binding pocket and the ring ansa directed toward the bottom of the bag. When the Hsp90 protein bound, has a GM Cf Shaped conformation Similar to that of ADP. 2A shows the main hydrogen-bonding interactions between GM and yeast Hsp90.31 Pay special attention to the carbamate group, the unerl Ugly for activity32, 33 and stabilizes the complex by binding directly and indirectly with Leu34, Asp79, Gly83, and Thr171.
GM is a potent cytotoxic agent, but clinical application has so far been prevented by a number of factors.29, 34 First, it Malotilate is difficult Hepatotoxizit t, which was connected to the ring and sets limits benzoquinone strict dosing. Second, it is metabolically and chemically unstable. In addition, it has a very low solubility require L In w In aqueous media formulations, the resulting DMSO. Consequently, a considerable effort into its structure Ver changed To the L Solubility of security, stability t, electricity and water made to improve. Many efforts have been made to modify the quinone ring to, In particular at the position 17 but also in the 19 position.35, 36 This is partly due to the relative ease with which the methoxy group C may be substituted 17 by nucleophilic amine.
If the substitution is at position 17 is generally in some F Cases observed, wherein the amine is very large or if the terms are used grease, then put 19 or 17.19 alkylamine be obtained.35 Up derivatives 36 in vitro Improved cell activity tw while the GM with the substitution of the methoxy C 17 with amino and alkylamino small groups.35 unimpeded activity takes t observed with the addition of an S acid group cha No alkylamino, may need during the recording of basic or hydroxyl group at cha Alkylamino was well tolerated. The derivative 17 17 desmethoxy-allylamino geldanamycin an IC50 31 nM for the inhibition of HER2 on SKBR3 breast cancer cells. 17 AAG has a strong activity t in vivo and is less toxic than GM.37, 38 17 AAG clinical trials in cancer patients in the United States and 42 UK.
39 Although initial attempts were disappointed; Traded, the development of an improved formulation of 17 AAG of Kos Pharmaceuticals Kosan reached 953, an agent with promising clinical activity Ten. Under the new formulation of encouraging clinical results in trastuzumab for HER2-positive breast cancer and refractory Rem myeloma, including bortezomib in multiple refractory patients.43 Despite the promising activity of t were found in clinical studies, 17 AAG has some RESTRICTIONS Website will, the their optimal clinical development nken to Descr. Lack of or reduced activity of t means that in some cells was determined by the Ausflu of drugs by multidrug-resistance elements or metabolic inactivation of these agents by nucleophiles such as glutathione observed. In addition, 17 AAG has a responsibility to the metabolism by the polymorphic cytochrome P450, CYP3A4 is likely to contribute to the pharmacokinetic variables. The compound is also reductive metabolism