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Development of distamycin-related DNA binding anticancer drugs
S Marchini1, M Broggini, C Sessa
1Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62- 20157 Milan, Italy.
Abstract:
The relatively low therapeutic index of the clinically used alkylating agents is probably related to the fact that these compounds cause DNA damage in a relatively unspecific manner, mainly involving guanine-cytosine rich stretches of DNA present in virtually all genes, therefore inducing unselective growth inhibition and death, both in neoplastic and in highly proliferative normal tissues. These considerations explain why in the last twenty years there has been an increasing interest in the identification of compounds which can target DNA with a much higher degree of sequence specificity than that of conventional alkylators. Minor groove binders (MGBs) are one of the most widely studied class of alkylating agents characterised by a high level of sequence specificity. The prototype of this class of drugs is distamycin A which is an antiviral compound able to interact, non-covalently, in theminor groove of DNA in A-T rich regions. It is not cytotoxic against tumour cells and thus has been used as a carrier for targeting cytotoxic alkylating moieties in theminor groove of DNA. The benzoyl mustard derivative of distamycin A, tallimustine, was found to be able to alkylate the N(3) of adenine in theminor groove of DNA only in the target hexamer 5'-TTTTGA or 5'-TTTTAA. Tallimustine was investigated in the clinic and was not successful because it causes severe bone marrow toxicity. The screening of other distamycin derivatives, which maintain antitumour activity and exhibit much lower toxicity against human bone marrow cells than tallimustine led to the identification of brostallicin (PNU-166196) which is currently under early clinical investigation. Although MGBs which bind DNA in A-T rich regions have not fulfilled the expectations, it is too early to draw definitive conclusions on this class of compounds. The peculiar bone-marrow toxicity observed in the clinic both with tallimustine or with CC-1065 derivatives is not necessarily a feature of all MGBs, as indicated by recent evidence obtained with brostallicin and other structurally unrelated MGBs (e.g., ET-743).
Insights
New DNA-targeting drugs, minor groove binders (MGBs), show promise for cancer therapy. Brostallicin, a novel MGB, demonstrates anti-tumor activity with reduced toxicity compared to earlier agents.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Conventional alkylating agents exhibit low therapeutic indices due to non-specific DNA damage, affecting both cancerous and normal proliferative tissues.
- This necessitates the development of sequence-specific DNA-targeting compounds to improve cancer treatment efficacy and reduce side effects.
- Minor groove binders (MGBs) represent a class of compounds designed for enhanced DNA sequence specificity.
Purpose of the Study:
- To explore the potential of MGBs as targeted anticancer agents.
- To identify novel MGBs with improved therapeutic profiles compared to existing drugs.
- To investigate the clinical efficacy and toxicity of emerging MGBs like brostallicin.
Main Methods:
- Screening of distamycin derivatives for antitumour activity and reduced bone marrow toxicity.
- Chemical modification of distamycin A to create targeted alkylating agents.
- Preclinical and early clinical evaluation of novel MGB compounds.
Main Results:
- Distamycin A derivatives, such as tallimustine, showed sequence-specific DNA alkylation but caused significant bone marrow toxicity.
- Brostallicin (PNU-166196), a novel MGB, exhibits antitumour activity with substantially lower toxicity to human bone marrow cells.
- Emerging evidence suggests that the toxicity profile of MGBs can vary significantly, with some compounds like brostallicin and ET-743 showing improved safety.
Conclusions:
- MGBs hold potential for developing more targeted and less toxic anticancer therapies.
- Brostallicin represents a promising candidate for further clinical investigation due to its favorable efficacy and toxicity profile.
- Further research into MGBs is warranted to fully elucidate their therapeutic potential and overcome limitations associated with earlier compounds.