CDK 8/19 Kinase Inhibitor RVU120 in Patients with AML or Higher-Risk MDS: Safety and Efficacy Results from New Dose Escalation Cohorts

Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of Cancer

“…We leveraged our extensive drug design experience − to identify a novel, potent CDK8/CDK19 inhibitor by structure-based optimization of RVU120. ,, It is noted that CDK8 and CDK19 showed over 80% sequence percent identity and that RVU120 inhibited kinase activities of both CDK8/CycC and CDK19/CycC complexes with comparable IC 50 values (4.4 nM for CDK8 vs 10.4 nM for CDK19). ,, With the lack of available crystal structure of CDK19 in protein data bank (PDB), we built the binding mode of RVU120 with CDK8 ( Figure A) based on the crystal structure of CDK8 (PDB ID: 5XS2) and the description of the RVU120/CDK8 complex (its PDB ID was previously not disclosed), assuming that structure modification of RVU120 based on CDK8 leads to the change of inhibition potency toward CDK8/CDK19 in a similar way. As previously described, the Br atoms of RVU120 form halogen bonds with the carbonyl group of D98 and the backbone NH of A100, respectively, and one Br atom also interacts with the π-system of Y99.…”

“…Furthermore, 12 did not raise any mutagenicity concerns, as determined by negative results in the Ames test. Given that clinical studies of RVU120 showed elimination change at higher doses resulting from time-dependent inhibition of CYP1A2, we furthermore evaluated CYP1A2 inhibition of 12 (Table ). Importantly, this revealed that CYP1A2 inhibition by 12 was only observed at significantly higher concentrations compared to RVU120 (IC 50 = 8.58 μM versus 0.16 μM), which trended well with decreased lipophilicity (cLogP of 4.14 for RVU120 vs 2.96 for 12 ) and planarity (Fsp 3 of 0.6 for RVU120 vs 0.7 for 12 ).…”