Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant
potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches
using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specificpromoter
derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity
against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual
structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the
isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies
illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to
be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as
readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity.
The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells
and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening
of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer
therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.
Keywords: Progression Elevated Gene-3, Sabutoclax, Apogossypol, BI-97C1, Gossypol, AP-1, PEA3, ETV4, E1AF, c-fos, c-jun, Cancer Terminator Virus
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