Polyamine Metabolic Inhibitor Technology
Our Polyamine Metabolic Inhibitor (PMI) platform is based upon exploitation of the key role played by polyamines in mammalian cells. Polyamines are positively charged, metabolically distinct entities within human cells that bind to and facilitate DNA replication, RNA transcription, and protein synthesis and function. Polyamines are critical for progression throughout the cell cycle, including playing a key role in cell division, as well as in programed cell death (apotosis).
Human cells contain three essential and naturally occurring polyamines: putrescine, spermidine, and spermine. Their synthesis and catabolism are tightly controlled within the cell. The requirement for polyamines and subsequent metabolism is upregulated in some tumor cells, including pancreatic ductal adenocarcinoma (PDA), as well as in many other human solid tumors. Consequently, polyamine function and metabolism are rational and important targets for therapeutic intervention. SBP-101 has been designed as a PMI synthetic analogue of spermine.
Earlier generations of PMIs are known to reduce polyamine pools by affecting key metabolic enzymes, resulting in both down-regulation of polyamine biosynthesis and up-regulation of polyamine catabolism. In preclinical models, it has been demonstrated SBP-101 uniquely causes polyamine metabolic inhibition through two interrelated pathways, but does not increase polyamine catabolism (Figure 1). Specifically, SBP-101 inhibits both S-adenosylmethionine decarboxylase 1 (AMD1) and ornithine decarboxylase 1 (ODC1), both key enzymes in polyamine biosynthesis, thus reducing the intracellular concentrations of polyamines and slowing or preventing the ability of targeted cells to grow and divide.
SBP-101 inhibits AMD1 and ODC1. The intracellular concentration of spermine is reduced and the concentrations of spermidine and putrescine are markedly reduced. Catabolic enzyme activity is essentially unchanged.
MAT: methionine adenosyltransferase, AMD1: S-adenosylmethionine decarboxylase, SRM: spermidine synthase, SMS: spermine synthase, ARG1: arginase, ODC1: ornithine decarboxylase, PAOX: polyamine oxidase, SSAT: spermidine/spermine N1-acetyltransferase.
Figure 1. Effect of SBP-101 on polyamine synthesis, catabolism and intracellular concentrations.
Preclinical Work: Preclinical studies showed SBP-101 to have significant efficacy against PDA in vitro and in vivo
Early studies by Prof. Bergeron at the University of Florida showed in animal models that treatment with SBP-101 inhibited polyamine synthetic but not catabolic enzymes, and reduced intracellular polyamine concentrations. Additional studies by Prof. Ashok Saluja at the University of Minnesota demonstrated that SBP-101 triggered caspase-3 activation, caused poly ADP-ribose polymerase (PARP) inhibition and induced programmed cell death (apoptosis) of pancreatic acinar and ductal cells. Further studies in vivo studies in models of human pancreatic cancer at three independent laboratories demonstrated that SBP-101 caused significant growth inhibition of implanted human pancreatic cancer cells.
Additional Research Programs
The company believes that PMI technology will have broad applicability beyond PDA. Early stage studies are underway in a variety of solid tumor models.