Project Marilyn: 9DS Xenograft Test

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Project Marilyn: 9DS Xenograft Test

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Project Marilyn: 9DS Xenograft Test

Isaac T Yonemoto indysci dot org

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

Adapted from Gerratana, 2012 (MRR)
  • Many PBDs have been discovered
  • The most potently antineoplastic PBDs are cardiotoxic
  • Neothramycin is not cardiotoxic and has limited clinical use

SJG-136

Adapted from Clingen, et. al., 2005 (NAR)
  • 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

NCI Cell line Cancer class Sibiromycin 9DS SR leukemia 25.1 3.2 NCI-H522 lung 120.2 7.6 MCF7 breast 131.8 8.5 SK-MEL-5 melanoma 154.9 14.1 GI50 (nm) for selected cell lines

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