Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1996-07-01
1998-03-17
Low, Christopher S. F.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562405, 560 34, 514 44, 424 936, C07C27500
Patent
active
057288682
DESCRIPTION:
BRIEF SUMMARY
This application is a filing under 35 U.S.C. 371 of PCT/GB94/01532 filed 15 Jul. 1994.
FIELD OF THE INVENTION
The present invention relates to prodrugs and their use in the treatment of tumours.
TECHNOLOGY REVIEW
The use of prodrugs represents a clinically very valuable concept in cancer therapy since, particularly where the prodrug is to be converted to an anti-tumour agent under the influence of an enzyme that is linkable to a monoclonal antibody that will bind to a tumour associated antigen, the combination of such a prodrug with such an enzyme monoclonal/antibody conjugate represents a very powerful clinical agent. This approach to cancer therapy, often referred to as "antibody directed enzyme/prodrug therapy" (ADEPT) is disclosed in WO88/07378.
More recently, a similar approach ("VDEPT") has been proposed where in place of an antibody/enzyme conjugate, tumour cells are targeted with a viral vector carrying a gene encoding an enzyme capable of activating a prodrug. The gene may be transcriptionally regulated by tumour specific promoter or enhancer sequences. The viral vector enters tumour cells and expresses the enzyme, in order that a prodrug is converted to an active drug only in the vicinity of the tumour cells (Huber et al, Proc. Natl. Acad. Sci. USA (1991) 18, 8039). Alternatively, non-viral methods for the delivery of genes have been used. Such methods include calcium phosphate co-precipitation, microinjection, liposomes, direct DNA uptake, and receptor-mediated DNA transfer. These are reviewed in Morgan & French Anderson, Annu. Rev. Biochem., 1993, 62;191. The term "GDEPT" (gene-directed enzyme prodrug therapy) is used to include both vital and non-viral delivery systems.
Although the GDEPT and ADEPT systems enhance the concentrations of anti-tumour agents which may be delivered to the site of a tumour, there is still a need to enhance the specificity of drug delivery. In both systems, active drug can be released into the environment of normal cells and cause damage. In the case of ADEPT, this can be caused by activation of prodrug by conjugates which have failed to localise at the tumour site. In GDEPT, transformation of normal tissue may lead to residual levels of expression of the enzyme away from the tumour or active drug may be released from tumour cells. .Although ways to increase the specificity of the ADEPT system is disclosed in WO89/10140, there remains a continuing need to improve the level of ADEPT and GDEPT specificity.
SUMMARY OF THE INVENTION
The present invention addresses such problems by the use of a novel class of prodrugs, which are prodrugs of protein tyrosine kinase (PTK) inhibitors. Some PTKs are known to be over-expressed by some types of tumours such as in breast and ovarian carcinomas, where the cErbB2 gene is over-expressed. Certain compounds have been found to be selective for PTKs and thus are relatively non toxic to cells which do not over-express PTKs.
The use of such compounds in ADEPT or GDEPT thus provides an increased level of specificity for the treatment of tumour cells. Prodrugs based upon PTK-inhibitors will be converted into PTK inhibitors primarily at the site of a tumour, but at the same time release of PTK-inhibitors at other sites or from the tumour will not cause cytotoxicity comparable to the release of non-specific cytotoxic drugs.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a compound which comprises a prodrug of a protein tyrosine kinase inhibitor (PTKi) linked to at least one protecting group said group being capable of being cleaved from said compound to release the protein tyrosine kinase inhibitor or a physiologically acceptable derivative of said prodrug.
The prodrug is of the general formula: at least one protecting group capable of being cleaved from the PTK inhibitor by the action of an enzyme.
Suitable PTKs include tyrphostins. Tyrphostins are low molecular weight (e.g. less than 2,000) styryl containing inhibitors of protein tyrosine kinase which are capable of binding to the subsite of
REFERENCES:
patent: 5405990 (1995-04-01), Burke et al.
Bagshawe et al. (1994); Annals of Oncology 5:879-891.
Melton et al. (Oct. 8, 1996); J. Natl. Cancer Inst., 88 (3-4):153-65.
Deonarain et al. (1994); Brit. J. Cancer, 70 (5):786-94.
Springer et al. (1995); Anti-Cancer Drug Design, 10:361-372.
Bashawe (Oct. 8, 1996); Molecular Medicine: 425-431.
Saperstein et al. (1989); Biochemistry, 28:5694-5701.
Gazit et al. (1989); J. Med. Chem., 32:2344.
Orkin et al. (1995); Report on Gene Therapy By NIH.
Marais Richard
Springer Caroline Joy
Cancer Research Campaign - Technology Limited
Low Christopher S. F.
Nguyen Dave T.
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