Comparison of the Cancer Gene Targeting and Biochemical Selectivities of All Targeted Kinase Inhibitors Approved for Clinical Use

Abstract

The anti-proliferative activities of all twenty-five targeted kinase inhibitor drugs that are in clinical use were measured in two large assay panels: (1) a panel of proliferation assays of forty-four human cancer cell lines from diverse tumour tissue origins; and (2) a panel of more than 300 kinase enzyme activity assays. This study provides a head-on comparison of all kinase inhibitor drugs in use (status Nov. 2013), and for six of these drugs, the first kinome profiling data in the public domain. Correlation of drug activities with cancer gene mutations revealed novel drug sensitivity markers, suggesting that cancers dependent on mutant CTNNB1 will respond to trametinib and other MEK inhibitors, and cancers dependent on SMAD4 to small molecule EGFR inhibitor drugs. Comparison of cellular targeting efficacies reveals the most targeted inhibitors for EGFR, ABL1 and BRAF(V600E)-driven cell growth, and demonstrates that the best targeted agents combine high biochemical potency with good selectivity. For ABL1 inhibitors, we computationally deduce optimized kinase profiles for use in a next generation of drugs. Our study shows the power of combining biochemical and cellular profiling data in the evaluation of kinase inhibitor drug action.

Kinase Inhibitor Profiling Reveals Unexpected Opportunities to Inhibit Disease-Associated Mutant Kinases

“…A small proportion of the analyzed mutant kinase/compound pairs overlap with previous large-scale screens (Tables S4 and S5); 1.9% of the mutant kinase/compound pairs overlapped with a previous study that utilized either ELISA or mobility shift assays to measure inhibition of kinase activity by 1 μM compound (Uitdehaag et al, 2014). For kinase/compound pairs that overlapped with our study (Table S4), there was general agreement, with the majority of overlapping pairs (66%) displaying either no inhibition or nearly complete inhibition of kinase activity in both studies (boxed regions in Figure 3A).…”

“…Kinase/compound pairs with intermediate levels of inhibition (values outside of the boxed regions in Figure 3A) showed greater discrepancies, likely due to the sensitivity of the assays to small differences in compound concentration near the IC 50 value or differences in the methods or protein constructs employed. Overall, 79% of the overlapping pairs exhibit either no inhibition, near complete inhibition, or show remaining kinase activity values within 20% of each other between the studies when the Uitdehaag et al (Uitdehaag et al, 2014) data is extrapolated to 500 nM compound concentration according to the Cheng-Prusoff equation (Figure 3A). …”

“…Here, we screened an overlapping collection of 183 small-molecule compounds against a panel of 76 mutated kinases derived from 21 cognate wild-type kinases. The resulting data set comprises over 13,000 mutant kinase-compound pairs, almost an order of magnitude larger than prior studies (Davis et al, 2011; Uitdehaag et al, 2014). These mutated kinases include many drug-resistant kinases and activating disease-associated mutant kinases.…”

PO-455 Epigenetic insights: resminostat regulates targets associated with the pathogenesis of cutaneous T cell lymphoma (CTCL)

“…1 Here we present the profiling of seventeen kinase inhibitors which have been approved since November 2014 in the Oncolines panel. 2 Material and methods The profiled agents include the ALK inhibitors ceritinib, brigatinib, and alectinib, the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib, the BTK inhibitors ibrutinib, and acalabrutinib, and nine other novel marketed inhibitors that were not profiled earlier. 2 The cell lines were screened in parallel in a high-throughput proliferation assay based on ATP-lite read-out, at 9 duplicate concentrations of each inhibitor.…”

Large-scale profiling of protein kinases for cellular signaling studies by mass spectrometry and other techniques

“…The substrate preference of each kinase can also be utilized to monitor individual kinase activities in a biological sample by using in vitro kinase reaction with substrate peptides, coupled with a peptide array [119][120][121][122], mobility shift assay [123,124] or mass spectrometry [125]. These methods have enabled high-throughput quantification of the activated kinome, which cannot be directly measured by transcriptome analysis, in a biological sample.…”