Dr. Eric Metzger
Center for Clinical Research
79106 Freiburg i. Br.
Exploitation of Oncogenic Mechanisms (EOM)
We identified the novel lysine methyltransferase KMT9 writing the chromatin mark histone H4 monomethylated at lysine 12 (H4K12me1). Depletion or enzymatic inactivation of KMT9 blocks not only proliferation of castration and enzalutamide-resistant prostate cancer cells and 3D organoids in vitro but also in xenograft and genetically engineered prostate tumours in vivo. Of note, KMT9 loss does not impair growth of non-transformed cells. The molecular mode of KMT9 action is independent of androgen receptor (AR) function thus, providing a promising, novel therapeutic paradigm for the treatment of castration-resistant prostate cancer (CRPC) exceeding the current gold standard of care. We developed high-potency drug-like KMT9 lead inhibitors displaying unprecedented specificity for KMT9.Here, we aim to develop our lead inhibitors to clinical candidates for phase I clinical testing.