Studies of BP-1-102, a Novel Direct Small-Molecule Inhibitor of Stat3 Demonstrates Substantial Anti-Myeloma Pre-Clinical Activity

• Published in: Blood 2010-11, Vol.116 (21), p.138-138
• Main Authors: Jimenez-Zepeda, Victor H, Li, Zhi Hua, Page, Brent DG, Zeng, Seda, Wei, Ellen, Leung-Hagesteijn, Chungyee, Turkson, James, Gunning, Patrick T., Trudel, Suzanne
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.138.138

Abstract 138 Stat3 is essential for transducing signals from extacellular stimuli, but also functions as a nuclear transcription factor required for regulating genes involved in proliferation, apoptosis, angiogenesis and invasion, in addition to genes encoding cytokines, chemokines and growth factors. In contrast to the transient nature of Stat3 activation in normal cells, many hematological tumors including multiple myeloma (MM) harbor constitutive Stat3 activity. In addition, activation of Stat3 is observed in MM bone marrow stroma cells (BMSCs), which is a major source of interleukin-6 (IL-6) that induces persistent activation of Stat3 in MM cells, thereby establishing a feedforward loop. Stat3 downstream target genes are critical to the dyregulated biological processes that promote MM cell growth, survival and induce chemoresistance, thus targeting JAK2/Stat3 signaling represents an important therapeutic target in MM. We describe here a novel, highly specific and potent small molecule inhibitor of Stat3 derived by molecular modeling of the phosphotyrosine (pY)-SH2 domain interactions in the Stat3:Stat3 dimerization, combined with in silico structural analysis of the Stat3 dimerization disruptor, S31-201. We present evidence from in vitro biochemical and biophysical studies that a structural analogs, BP-1-102 directly interacts with Stat3′s SH2 domain, with high affinity and disrupts the binding of Stat3 to a high affinity pY-peptide, GpYLPQTV-NH2, with IC50′s of 19 mM (BP-1-102) making this one of the most effective disruptors of Stat3 protein-phosphopeptide complexation events by a non-phosphorylated small molecule. We evaluated the activity of BP-1-102 in a series of pre-clinical models of MM. Analyses against a panel of 14 genetically diverse human myeloma cells lines (HMCLs) revealed that BP-1-102 suppressed myeloma cell growth in a dose-dependent fashion. After 72 h of in vitro exposure, the IC50 values ranged from 4.5–9.5 mM in responsive cell lines. Increased sensitivity to BP-1-102 was observed in HMCLs demonstrating a high IL-6/Stat3 gene expression signature. As expected, chemically optimized BP-1-102 demonstrated greater inhibitory potency then its parent compound, SF-1-66 (IC50 values 18–43.1 mM). BP-1-102 demonstrated a good therapeutic window failing to inhibit normal bone marrow (BM)-derived CD34 colony formation at doses up to 20 mM. Similar potent activity was observed against primary MM cells. Exposure of 6 patient derived BM mononucl