Novel ubiquitin ligases as therapeutic targets

Abstract

The present invention relates to the discovery, identification and characterization of nucleotides that encode novel substrate-targeting subunits of ubiquitin ligases. The invention encompasses nucleotides encoding novel substrate-targeting subunits of ubiquitin ligases: FBP1, FBP2, FBP3, FBP4, FBP5, FBP6, FBP7, FBP8, FBP9, FBP10, FBP11, FBP12, FBP13, FBP14, FBP15, FBP16, FBP17, FBP18, FBP19, FBP20, FBP21, FBP22, FBP23, FBP24, and FBP25, transgenic mice, knock-out mice, host cell expression systems and proteins encoded by the nucleotides of the present invention. The present invention relates to screening assays that use the novel substrate-targeting subunits to identify potential therapeutic agents such as small molecules, compounds or derivatives and analogues of the novel ubiquitin ligases which modulate activity of the novel ubiquitin ligases for the treatment of proliferative and differentiative disorders, such as cancer, major opportunistic infections, immune disorders, certain cardiovascular diseases, and inflammatory disorders. The invention further encompasses therapeutic protocols and pharmaceutical compositions designed to target ubiquitin ligases and their substrates for the treatment of proliferative disorders.

Description

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Application No. 60 / 098,355, filed Aug. 28, 1998, Application No. 60 / 118,568, filed Feb. 3, 1999, and Application No. 60 / 124,449 filed Mar. 15, 1999, the contents of which are incorporated herein by reference in their entirety.1. INTRODUCTION [0002] The present invention relates to the discovery, identification and characterization of nucleotide sequences that encode novel substrate-targeting subunits of ubiquitin ligases. The invention encompasses nucleic acid molecules comprising nucleotide sequences encoding novel substrate-targeting subunits of ubiquitin ligases: FBP1, FBP2, FBP3a, FBP3b, FBP4, FBP5, FBP6, FBP7, FBP8, FBP11, FBP12, FBP13, FBP14, FBP15, FBP17, FBP18, FBP20, FBP21, FBP22, FBP23, AND FBP25, transgenic mice, knock-out nice, host cell expression systems and proteins encoded by the nucleotides of the present invention. The present invention relates to screening assays to identify potential therapeu...

AI Technical Summary

Benefits of technology

The present invention is about novel F box proteins and their interactions with other components of the ubiquitin ligase complexes. These proteins have been identified and characterized based on their interaction with other components of the complex. The invention also includes methods for identifying compounds that modulate the activity of these proteins and their use as therapeutic agents for the treatment of proliferative and differentiative disorders. The invention also includes the use of transgenic mice expressing these proteins for identifying potential substrates and the development of agonists and antagonists of the proteins.

Problems solved by technology

When positive signals overcome or when negative signals are absent, the cells multiply too quickly and cancer develops.

However, all this mechanism goes awry in tumors leading to the excessive accumulation of positive signals (oncogenic proteins), or resulting in the abnormal degradation of negative regulators (tumor suppressor proteins).

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