Potent anti-leukemic activity of a specific cyclin-dependent kinase 9 inhibitor in mouse models of chronic lymphocytic leukemia

// Joachim R. Gothert 1 , Roze Imsak 1 , Michael Mollmann 1 , Stefanie Kesper 1 , Maria Gobel 1 , Ulrich Duhrsen 1 , Arne Scholz 2 , Ulrich Lucking 2 , Matthias Baumann 3 , Anke Unger 3 , Carsten Schultz-Fademrecht 3 , Bert Klebl 3 , Jan Eickhoff 3 , Axel Choidas 3 and Jan Durig 1 1 Department of Hematology, West German Cancer Center (WTZ), University Hospital Essen, Essen, Germany 2 Bayer AG, Pharmaceuticals, Drug Discovery, Berlin, Germany 3 Lead Discovery Center GmbH (LDC), Dortmund, Germany Correspondence to: Joachim R. Gothert, email: joachim.goethert@uk-essen.de Keywords: chronic lymphocytic leukemia; cyclin-dependent kinase 9; MEC-1 cell line; TCL1 transgenic mice; NSG mice Received: August 16, 2017      Accepted: April 07, 2018      Published: May 29, 2018 ABSTRACT Onset of progression even during therapy with novel drugs remains an issue in chronic lymphocytic leukemia (CLL). Thus, there is ongoing demand for novel agents. Approaches targeting cyclin-dependent kinases (CDK) have reached the clinical trial stage. CDK9 mediating RNA transcriptional elongation is the evolving pivotal CLL CDK inhibitor target. However, more CDK9 selective compounds are desirable. Here, we describe the CDK9 inhibitor LDC526 displaying a low nanomolar biochemical activity against CDK9 and an at least 50-fold selectivity against other CDKs. After demonstrating in vitro MEC-1 cell line and primary human CLL cell cytotoxicity we evaluated the LDC526 in vivo effect on human CLL cells transplanted into NOD/scid/γc null (NSG) mice. LDC526 administration (75 mg/kg) for 5 days resulted in a 77% reduction of human CLL cells in NSG spleens compared to carrier control treatment. Next, we longitudinally studied the LDC526 impact on circulating CLL cells in the TCL1 transgenic mouse model. LDC526 (50 mg/kg) administration for two days led to a 16-fold reduction of blood CLL cell numbers. Remarkably, residual CLL cells exhibited significantly increased intracellular BCL-2 levels. However, the LDC526 cytotoxic effect was not restricted to CLL cells as also declining numbers of normal B and T lymphocytes were observed in LDC526 treated TCL1 mice. Taken together, our in vivo data provide a strong rational for continued LDC526 development in CLL therapy and argue for the combination with BCL-2 inhibitors.