title: 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.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hedvat
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Keetae
authors.initials: K
authors.lastname: Kim
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Shibu
authors.initials: S
authors.lastname: Thomas
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Quinn
authors.forename: Regina A
authors.initials: RA
authors.lastname: Oyesanya
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Kegelman
authors.forename: Upneet K
authors.initials: UK
authors.lastname: Sokhi
authors.forename: Siddik
authors.initials: S
authors.lastname: Sarkar
authors.forename: Eda
authors.initials: E
authors.lastname: Erdogan
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Menezes
authors.forename: Praveen
authors.initials: P
authors.lastname: Bhoopathi
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Bainan
authors.initials: B
authors.lastname: Wu
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Paul W
authors.initials: PW
authors.lastname: Diaz
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000191:economics / Q000379:methods*; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D006072:Gossypol