Pipeline

The S*BIO R&D team has assembled a comprehensive toolkit around HDACs, comprising enzyme isoforms and molecular tools, which enable the study of the involvement of those isozymes in different disease indications and patient populations. These in-house research efforts have led to the identification of SB939, a best-in-class HDAC inhibitor with superior physicochemical and pharmacodynamic properties.

HDACs play a key role in the epigenetic regulation of gene expression by remodeling chromatin. HDACi enhances transcription and results in a variety of cellular responses that lead to the inhibition of tumor growth.

In 2007, S*BIO initiated a Phase 1 clinical trial in Singapore with SB939, the first drug discovered and developed in Singapore; Phase 1 trials have also been conducted in USA and Canada. The trials are testing SB939 for safety, pharmacokinetics and pharmacodynamics in both solid and hematological tumors. Preliminary results are encouraging and have confirmed the superior compound exposure and safety of SB939 demonstrated in preclinical studies.

S*BIO has two more HDAC inhibitors in its portfolio; a back-up compound, SB1304, from the same chemical series as SB939, and a follow-up compound, SB1354, from a different chemical series.

Histone deacetylases (HDACs) and histone acetyltransferase (HATs) play a key role in epigenetic regulation of gene expression by regulating chromatin structure. Acetylation of the lysine residues by the HATs at the N-termini of histone proteins removes positive charges, thereby reducing the affinity between histones and the negatively charged DNA, resulting in the opening-up of the chromatin structure. This makes it easier for the transcriptional machinery to access the DNA, enhancing transcription. Conversely, deacetylation by the HDACs closes the chromatin structure leading to a repression of gene transcription. In normal cells, HDACs and HATs together control the histone acetylation level to maintain a balance. In diseases such as cancer, this regulation can be disturbed. HDAC inhibitors (HDACi) cause accumulation of acetylated histones, enhance transcription and result in changes of a variety of cellular responses including differentiation, proliferation, migration, survival and response to metabolic and hypoxic stress. Tumor cells are more susceptible than normal cells to the anti-proliferative and pro-apoptotic effects of HDACi.

Zolinza (vorinostat, SAHA), the first HDACi approved by the FDA in 2006 for the treatment of cutaneous T-cell lymphoma, validated HDAC as a target for cancer therapy. SAHA and other HDAC inhibitors have been evaluated in clinical trials not only for various liquid and solid tumors but also for non-oncology indications such as myeloproliferative diseases, myelodysplastic syndrome (MDS), Huntington’s disease, autoimmune lymphoproliferative syndrome (ALPS) and HTLV-1 associated myelopathy (HAM/TSP) and HIV. However, therapeutic benefit has been limited due to the poor pharmaceutical properties and toxicities of these earlier compounds.

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