Abstract 980: BAY-299, a novel chemical probe for in-depth analysis of the function of the bromodomain proteins BRPF2 and TAF1
Bouche L., Christ CD., Siegel S., Tallant C., Fernández-Montalván AE., Huber KV., Pütter V., Müller S., Fedorov O., Laak AT., Sugawara T., Stöckigt D., Meier J., Holton SJ., Hartung IV., Haendler B.
Abstract With the exception of the bromodomain and extra-terminal domain BET subgroup, little is known about the role of bromodomain (BD) containing proteins in cancer so that there is a dire need for chemical probes addressing other family members. The bromodomain and PHD-finger (BRPF) family encompasses three paralogs, BRPF1, BRPF2 and BRPF3, which are all found in histone acetyltransferase (HAT) complexes. BRPF2 is a scaffold protein and its knock-out leads to embryonic lethality at E15.5, potentially due to its role in embryonic stem cell differentiation. Here we present the structure-activity relationship (SAR) and characterization of the first selective BRPF2 chemical probe BAY-299, with additionnal strong activity at TAF1, a major component of the basal transcription initiation complex TFIID. BAY-299 shows in vitro activity for BRPF2 (IC50 = 67 nM) and TAF1 second bromodomain (BD2; IC50 = 8 nM) in the TR-FRET assay, as well as in the cellular NanoBRET assay [IC50 (BRPF2) = 575 nM; IC50 (TAF1 BD2) = 825 nM]. To the best of our knowledge BAY-299 is the only disclosed inhibitor showing BRPF2 selectivity over its two paralogues BRPF1 and BRPF3. It belongs to the 1,3-benzimidazolone scaffold and bears a novel substitution which is responsible for its high BRPF2 selectivity and also for its inactivity on BET BDs. The dual inhibitory properties of BAY-299 against BRPF2 and TAF1 make it an ideal research tool for further investigation of these two proteins in physiological and pathological processes. Citation Format: Lea Bouche, Clara D. Christ, Stephan Siegel, Cynthia Tallant, Amaury E. Fernández-Montalván, Kilian V. Huber, Verra Pütter, Susanne Müller, Oleg Fedorov, Antonius ter Laak, Tatsuo Sugawara, Detlef Stöckigt, Julia Meier, Simon J. Holton, Ingo V. Hartung, Bernard Haendler. BAY-299, a novel chemical probe for in-depth analysis of the function of the bromodomain proteins BRPF2 and TAF1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 980. doi:10.1158/1538-7445.AM2017-980