Project Marilyn: 9DS Xenograft Test

History of Sibiromycin

• Discovered in 1970s by Soviet researchers in Siberia
• Antimicrobial activity "bioassay"
  

  Adapted from Li, et. al, 2009 (AEM)
• Found to have antineoplastic activity
• Cardiotoxic in animal models

Mechanism of Sibiromycin Action

• Reactive imine group alkylates exocyclic amine of DNA Guanine bases
• Cationic sugar extends and binds to the phosphodiester backbone*
• Twist imparted by chirogenic center makes the 6-7-5 ring fit into the minor groove
  • Evades base excision repair system

Sibiromycin Family

• Many PBDs have been discovered
• The most potently antineoplastic PBDs are cardiotoxic
• Neothramycin is not cardiotoxic and has limited clinical use

SJG-136

• Synthetic compound developed by Spirogen
• Presumably Similar Mechanism
• Single-digit nanomolar in vitro activity
• Very mild side effects
  • water retention

Mutasynthetic Scheme

Mutasynthetic Scheme

Synthesis Procedure

• 48 hours of culture
• Centrifugation
• Filtration
• Wash/Extraction
• Concentration
• Silica Gel Chromatography
• Size Exclusion Chromatography
• ~2.5mg/L yield

Results from Part I

Project Marilyn Objectives

• Production of 10+mg of 9DS
• Delivery of 9DS to a xenograft CRO
• Completion of a 5-armed xenograft study

Project Marilyn Secondary Objectives

• Identification and testing of a new compound, "Satoshimycin"
  
• Correction of Tm measurements

Project Marilyn Timeline

• Lab Opening: Imminent (2-3 weeks)
• Piloting batch of 9DS completed: 2 mo
• Initial Analytic (NMR, MS) of 9DS completed: 3 mo
• Delivery of 9DS to CRO: 6 mo
• Completion of xenograft by CRO: 12 mo
• Identification of Satoshimycin and other compounds: 1 mo
• Analysis, NCI-60 of Satoshimycin: 6 mo