Zurück zur Übersicht
| Oncogene. 2018 Mar 1. doi: 10.1038/s41388-018-0150-2. pii: 10.1038/s41388-018-0150-2 |
| The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML. |
| Gerlach D1, Tontsch-Grunt U2, Baum A3, Popow J4, Scharn D5, Hofmann MH6, Engelhardt H7, Kaya O8, Beck J9, Schweifer N10, Gerstberger T11, Zuber J12, Savarese F13, Kraut N14 |
 Author information
|
|
Abstract Bromodomain and extra-terminal (BET) protein inhibitors have been reported as treatment options for acute myeloid leukemia (AML) in preclinical models and are currently being evaluated in clinical trials. This work presents a novel potent and selective BET inhibitor (BI 894999), which has recently entered clinical trials (NCT02516553). In preclinical studies, this compound is highly active in AML cell lines, primary patient samples, and xenografts. HEXIM1 is described as an excellent pharmacodynamic biomarker for target engagement in tumors as well as in blood. Mechanistic studies show that BI 894999 targets super-enhancer-regulated oncogenes and other lineage-specific factors, which are involved in the maintenance of the disease state. BI 894999 is active as monotherapy in AML xenografts, and in addition leads to strongly enhanced antitumor effects in combination with CDK9 inhibitors. This treatment combination results in a marked decrease of global p-Ser2 RNA polymerase II levels and leads to rapid induction of apoptosis in vitro and in vivo. Together, these data provide a strong rationale for the clinical evaluation of BI 894999 in AML. |
|
Publikations ID: 29491412 Quelle: öffnen |
Author information
Schnellinfo
-- Cancer Care
-- Kliniken und Partner
-- CCC Cancer School
-- Young CCC
-- CCC Tumorboards
-- CCC Forschungscluster
-- CCC Units
-- CCC Platforms
-- SOPs / Leitlinien
-- Kontakt
Featured
