As a master regulator of cell signaling and tumorigenesis, signal transducer and activator of transcription 3 (Stat3) protein has emerged at the forefront of anti-cancer drug development. Abnormal Stat3 activity has been demonstrated in a wide variety of human cancers including leukemia, lymphoma, multiple myeloma, glioblastoma and cancers of the pancreas, breast, prostate, and ovary. Constitutive Stat3 activation interferes with normal cell cycling and causes the accumulation of anti-apoptotic proteins. This renders malignant cells resistant to naturally occurring apoptotic cues and allows them subject to proliferate rapidly. Cancer cells become reliant on increased levels of Stat3 activity are vulnerable to therapeutic intervention through Stat3 inhibition. In healthy cells, Stat3 activity is transient and non-essential, thus, inhibiting Stat3 presents an avenue for the development of novel cancer therapeutic agents.

Our approach involves the interruption of several critical Stat3 functions by occupation of the SH2 domain with small molecule inhibitors. Stat3's SH2 domain is a key component in the Stat3 signaling pathway as it not only facilitates activation of monomeric Stat3 but also moderates the formation of the transcriptionally active Stat3:Stat3 homodimer.

Our research groups have conducted a thorough structure-activity relationship on a known Stat3-SH2 domain binder (S3I-201) and have discovered several more potent and more drug-like Stat3 inhibitors. Most recently, we have utilized a tetrapodal scaffold that has allowed more complete occupation of the SH2 domain and resulted in greatly improved binding affinity. These novel compounds effectively displace an SH2 domain-binding peptide probe, prevent Stat3 phosphorylation in cell line models and suppress Stat3 target gene expression at near-nanomolar concentrations. Our latest Stat3 inhibitors are effective across a wide variety of human cancers and exhibit a 10–20-fold improvement in cellular EC50 values over the parent compound, S3I-201.

Remarkable activity is observed in mouse xenograft models of human breast cancer where nearly complete inhibition of tumor growth is observed at a dosing of 3 mg/kg daily. Furthermore, recent experiments demonstrate the same potent activity when the drug is administered by oral gavage, with plasma drug concentrations reaching 20 μM. Preliminary investigations have also shown that our lead compounds can re-sensitize malignant cells that are resistant to conventional chemotherapeutics agents.

We present our newest library of Stat3 inhibitors, which holds great promise in the fight against cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A121.