The Syndax Approach

Syndax is employing epigenetics—a novel way to control gene regulation—to address unmet needs in cancer due to the problem of resistance. Epigenetic alterations of gene expression are now known to initiate cancer, influence its progression and contribute to drug tolerance. Acquired resistance is believed to result in part from a continuous gradient of reversible epigenetic and permanent genetic changes.1

Syndax is employing epigenetic drugs to selectively target reversible epigenetic changes in cancer cells that lead to the development of drug tolerance to certain targeted therapies. Two such modifications are the acetylation of histones and the methylation of DNA, both of which can affect DNA transcription and expression. Our lead product candidate, entinostat, is a novel inhibitor of histone deacetylases, enzymes which have been shown to influence the ability of histones to regulate gene expression. Using drugs that can modify or reverse epigenetic changes in cancer-associated gene expression.

Syndax is using a combination approach with entinostat to epigenetically modulate the development of drug tolerance to important classes of cancer drugs. Two such drugs include endocrine agents that block the production of estrogen which drives tumor growth in estrogen receptor positive postmenopausal women with metastatic breast cancer (MBC) and tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) which compete with the growth factor that stimulates tumor proliferation in non-small cell lung cancer (NSCLC). In both cases epigenetic changes in these tumor types- which can be reversed by entinostat- have been show to correlate with the development of resistance to these drugs in preclinical animal models.1,2,3,4

1. Drug tolerant cells (indicated in red) with altered chromatin state emerge de novo as a small fraction of drug sensitive (indicated in blue) tumor cell population.
2. Drug sensitive cells are killed but the drug tolerant persistor (DTP) cell population survives.
3. Addition of HDAC inhibitor (HDACi) prevents or delays the emergence of drug tolerant clones.1






DNA exists in the nucleus of a cell in compact structures called chromatin which includes the DNA itself and the histones around which the DNA is wrapped. The ability of a given gene to be expressed is partly dependent on whether the DNA is accessible or inaccessible to the gene expression machinery. The accessibility is determined by modifications to the DNA or the histones, i.e. epigenetic modifications which generate a closed, tightly wrapped structure or an open, loosely wrapped structure.