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Targeting DNA: A Modular Approach Using Structure-Based Design and Combinatorial Libraries
The University of Texas M D Anderson Cancer Center, Holcombe Boulevard 1515, Houston, TX 77030, United States
The ongoing explosion of genomic information is creating an astounding increase in the number of biological targets for new drug discovery. Massive efforts by university research centers and the pharmaceutical industry to identify gene targets are driving the development of drugs that can control the expression of specific genes. Current techniques involving antisense approaches or proteins have inherent problems such as the large mass, rapid metabolism, and reduced cellular uptake of these compounds. These drawbacks can be overcome by the use of small-molecule DNA-binding agents displaying high DNA affinity and sequence specificity that can also penetrate cell membranes.
To exploit this concept, we developed a modular design approach that combines intercalation and groove binding modes into molecules with the requisite binding site size to impart meaningful sequence selectivity. Such an approach, which can be visualized as playing molecular "Lego" with DNA, allows libraries of compounds to be built using rational structure-based and combinatorial design. We used an anthracycline-antibiotic scaffold to develop our modular approach, which has provided the key intercalating and minor groove-binding modules that can be exploited for their known sequence-binding preferences and their proven clinical worth.
Our new strategy has succeeded in creating four related but distinct classes of novel DNA-targeting agents that might have significant medical application. These four classes include (1) 6-bp-long DNA-binding agents with bisintercalating and groove-binding properties and picomolar DNA binding affinity that can act as small-molecule modulators of gene expression, (2) WP900, the first molecule that binds selectively to Z-DNA, (3) medium-affinity DNA-binding anticancer agents that have distinct advantages over existing chemotherapeutic drugs, and (4) base-specific highly cytotoxic DNA-crosslinking agents. Our lead drug (WP744) is in clinical studies for brain tumors, and our second drug candidate (WP760), which targets selectively malignant melanoma, is in preclinical evaluation.
Presentation: invited lecture at 18th Conference on Physical Organic Chemistry, Plenary session, by Waldemar Priebe
See On-line Journal of 18th Conference on Physical Organic Chemistry
Submitted: 2006-06-06 08:27 Revised: 2009-06-07 00:44