Polymer-conjugated MetAP2 inhibitors, and therapeutic methods of use thereof

摘要

One aspect of the invention provides polymer conjugated MetAP2 inhibitors. While not being bound by any particular theory, it is believed that coupling the MetAP2 inhibitory core via the linkers described herein provides compounds with superior efficacy to the parent small molecules and superior pharmacokinetic profiles. In one aspect of the invention, the polymer conjugated MetAP2 inhibitors are useful in methods of treating disease, comprising administering to a subject in need thereof a therapeutically effective amount of a polymer conjugated MetAP2 inhibitor.

主权项

1. A method of treating lung cancer, colon cancer or melanoma in a subject, comprising administering to the subject an effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:R4 is H or —C1-C6 alkyl;R5 is H or —C1-C6 alkyl;R6 is C2-C6 hydroxyalkyl;Z is —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X—Y—C(O)—W;AA1 is glycine, alanine, or H2N(CH2)mCO2H;AA2, AA3 and AA4 are each independently selected from a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine;AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2)mCO2H;Q-X—Y iswherein p indicates the point of attachment to the polymer moiety and w indicates the point of attachment to the moiety W; andW isx is an integer 1 to about 450;y is an integer 1 to about 30;m is 2, 3, 4 or 5; andn is an integer 1 to about 50.