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

Abstract

Summary Small-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant, mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases including ALK, LRRK2, RET, and EGFR as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRα as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development.

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

“…2012; Frett et al 2014; Sun et al 2014; Schwartz et al 2015; Dunna et al. 2015; Zhang et al 2016; Han et al 2016; Duong-Ly et al 2016; Mologni et al 2017). In the following section, we will focus on those compounds that have demonstrated, in protein-based or cell-based assays, RET inhibitory activity in the low nanomolar range and for which biochemical selectivity towards other kinases has been systematically explored by enzymatic assays.…”

Informatics Approaches for Predicting, Understanding, and Testing Cancer Drug Combinations

“…In the same year, another major large-scale functional profiling was reported for 178 kinase inhibitors and 300 wild-type kinases, where the enzymatic activities were measured at 500 nM of the compounds in the presence of 10 μM ATP [32]. A more recent functional screen using the same assay format has been focused on 76 clinically important mutant kinases and 183 compounds [33]. Despite the differences in the binding and functional assays, the overall consistency of these studies seems reasonably good, indicating that the binding affinity of a drug-target interaction can predict its inhibition of catalytic activity [25, 34].…”

“…Treating of a chronic myeloid leukemia patient with axitinib resulted in a rapid clearance of BCR-ABL1(T315I)-positive cells from the bone marrow, providing further clinical evidence for axitinib’s potential to be “repositioned” as an effective drug for leukemia [37]. In the more recent screening of 183 kinase inhibitors against 76 mutant kinases, an FDA-approved EGFR inhibitor erlotinib has been shown to inhibit the T674I mutant of platelet-derived growth factor receptor alpha (PDGFRα) which also induces the imatinib resistance in many cancers [33]. …”

Discovery of wtRET and V804MRET Inhibitors: From Hit to Lead

“…Af ew more compounds are under investigation, [12] including a potent inhibitor of the V804M mutant. [13] Different strategies have been pursued for the identification of novel RET inhibitors, such as drug repurposing, [14] kinase profiling, [15] andu se of multicomponent reaction libraries. [16] In this work, we report our efforts in the development of novel analogues of compound 1 endowed with sub-micromolar RET inhibitory potency.A ccording to our previous results, [9] we hypothesized that 1 would bind the inactive kinase conformation.…”