A novel drug target and peptide(s) designed to inhibit protein synthesis by specifically preventing formation of the 43S preinitiation complex

DESCRIPTION OF THE INVENTION:

The invention relates to a novel drug target and peptide(s) designed to inhibit protein synthesis by specifically preventing formation of the 43S preinitiation complex. In vitro studies have confirmed the ability of the peptide(s) to inhibit de novo protein synthesis. This invention is particularly applicable to the treatment of proliferative diseases such as cancer.

The invention covers the (and related) polypeptides, pharmaceutical compositions comprising the polypeptides, a method of modulating mRNA translation, as well as their use in treating a disorder in a subject. Additional claims are directed to alternative methods of modulating the activity of the novel drug target as a means of inhibiting mRNA translation.

BACKGROUND:

The global cancer market was valued at US$35.2 billion in 2006 and is projected to continue to experience a 5.75% annual growth rate. New chemical or biological entities which have entered the cancer market in the last decade (“new innovatives”) are the fastest growing segment of the market, which now make up 62.5% of sales, and will be a key driver for new sales growth across the pharmaceutical market as a whole. Modulation of transcription has traditionally been a primary focus for cancer therapies; however, there is increasing evidence for an essential role of differential protein synthesis in cancer. Over the past decade the regulation of protein synthesis has become an important and promising area for the development of novel anticancer drugs.

Translation initiation factors have received increased attention recently as therapeutic targets as a result of studies in which overexpression of translation initiation factors was shown to be involved in neoplastic transformation. Two stages of the initiation process have been of particular interest: 1) assembly of the 43S preinitiation complex, and 2) recruitment of mRNA. Either step can be rate limiting. The protein kinase mTOR (mammalian target of Rapamycin) is a critical regulator protein involved in the signal cascade necessary for mRNA recruitment. Several mTOR signaling inhibitors are in preclinical and clinical development. A recognized limitation of this approach is that mTOR is an indirect regulator of protein synthesis. There is a need for the development of therapeutics that specifically and directly inhibit the activity of translation initiation factors.

POTENTIAL ADVANTAGES/USES:

The present invention provides a novel drug target and means to directly inhibit protein synthesis. This invention may be expanded from the cancer field and applied to the treatment of other proliferative disorders namely cardiac hypertrophy/failure, coronary artery restenosis and psoriasis. This will be of interest to pharmaceutical and biotechnology companies developing therapeutics for proliferative diseases.

Key Words: cancer, signal cascade, 43S preinitiation complex, protein synthesis, peptide, mRNA translation, proliferation

Ref. #s: UWO-AF-014; UWO-AI-01

Preclinical

US provisional application

Available for license and/or collaborative approach