Screening for novel HDAC-inhibitors targeting epigenetically dysregulated cell differentiation in triple-negative breast cancer
Kulik A.1, Esser K.1, Niederacher D.1, Neubauer H.1, Kurz T.2, Fehm T.1
1Heinrich-Heine-University of Düsseldorf, Department of Obstetrics and Gynecology, Life Science Center, Düsseldorf, Deutschland, 2Heinrich-Heine-University of Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Düseldorf, Deutschland

Purpose: Targeting tumor specific epigenetic deregulations by activating silenced cellular differentiation programs is a promising strategy for tumor treatment. Epigenetic-acting agents are supposed to potently reduce solid cancer cell tumorigenicity and to render cells more prone to common therapies. Histone deacetylase (HDAC) inhibitors represent one innovative class of epigenetic drugs known to induce differentiation in distinct cancer cells.
Methods: We analysed an in-house library of 20 newly developed HDAC-inhibitors by a cell-based phenotypic high-throughput screening system which allows the identification of potential epigenetic-acting agents via the quantification of two innovative differentiation markers. MDA-MB-231 cells were used as in vitro model for complex epigenetic deregulations leading to an early differentiation arrest. Differentiation-inducing potency of the identified substances was validated by quantifying the expression of characterized differentiation markers by qRT-PCR analysis and compared to clinically relevant HDAC inhibitors.
Results: Testing a databank of 20 novel HDAC inhibitors identified two substances as possible hit-candidates. These substances showed a higher pharmacological efficacy compared to current clinical HDAC inhibitors.
Conclusions: We have successfully discovered two new HDAC inhibitors inducing differentiation in triple negative MDA-MB-231 cells. Further studies will be performed to optimize pharmacological potency and to investigate their potential suitability for anti-tumor drug development.