Selected approaches for rational drug design and high throughput screening to identify anti-cancer molecules.

Abstract

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.

• Authors: Michael Hedvat, Luni Emdad, Swadesh K Das, Keetae Kim, Santanu Dasgupta, Shibu Thomas, Bin Hu, Shan Zhu, Rupesh Dash, Bridget A Quinn, Regina A Oyesanya, Timothy P Kegelman, Upneet K Sokhi, Siddik Sarkar, Eda Erdogan, Mitchell E Menezes, Praveen Bhoopathi, Xiang-Yang Wang, Martin G Pomper, Jun Wei, Bainan Wu, John L Stebbins, Paul W Diaz, John C Reed, Maurizio Pellecchia, Devanand Sarkar, Paul B Fisher
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 12 Issue 9 Pg. 1143-55 (Nov 2012) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 22931411 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)

Chemical References

• Antineoplastic Agents
• Gossypol

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Drug Design
• Drug Screening Assays, Antitumor (economics, methods)
• Gossypol (analogs & derivatives, pharmacology)
• High-Throughput Screening Assays
• Humans
• Neoplasms (drug therapy, genetics)
• Promoter Regions, Genetic (drug effects)