Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules

Title:Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules

Volume: 12 Issue: 9

Author(s): Siddik Sarkar, Paul B. Fisher, Devanand Sarkar, Maurizio Pellecchia, John C. Reed, Paul W. Diaz, John L. Stebbins, Bainan Wu, Jun Wei, Martin G. Pomper, Xiang-Yang Wang, Praveen Bhoopathi, Mitchell E. Menezes, Eda Erdogan, Michael Hedvat, Upneet K. Sokhi, Timothy P. Kegelman, Regina A. Oyesanya, Bridget A. Quinn, Rupesh Dash, Shan Zhu, Bin Hu, Shibu Thomas, Santanu Dasgupta, Keetae Kim, Swadesh K. Das and Luni Emdad

Affiliation:

Keywords: Progression Elevated Gene-3, Sabutoclax, Apogossypol, BI-97C1, Gossypol, AP-1, PEA3, ETV4, E1AF, c-fos, c-jun, Cancer Terminator Virus

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.

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Sarkar Siddik, B. Fisher Paul, Sarkar Devanand, Pellecchia Maurizio, C. Reed John, W. Diaz Paul, L. Stebbins John, Wu Bainan, Wei Jun, G. Pomper Martin, Wang Xiang-Yang, Bhoopathi Praveen, E. Menezes Mitchell, Erdogan Eda, Hedvat Michael, K. Sokhi Upneet, P. Kegelman Timothy, A. Oyesanya Regina, A. Quinn Bridget, Dash Rupesh, Zhu Shan, Hu Bin, Thomas Shibu, Dasgupta Santanu, Kim Keetae, K. Das Swadesh and Emdad Luni, Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules, Anti-Cancer Agents in Medicinal Chemistry 2012; 12 (9) . https://dx.doi.org/10.2174/187152012803529709