An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic

Abstract

Targeting kinases is central to drug-based cancer therapy but remains challenging because the drugs often lack specificity, which may cause toxic side effects. Modulating side effects is difficult because kinases are evolutionarily and hence structurally related. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a proportion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. Motivated by this finding, we made a modification to imatinib that hampers Bcr-Abl inhibition; refocuses the impact on the C-Kit kinase; and promotes inhibition of an additional target, JNK, a change that is required to reinforce prevention of cardiotoxicity. We established the molecular blueprint for target discrimination in vitro using spectrophotometric and colorimetric assays and through a phage-displayed kinase screening library. We demonstrated controlled inhibitory impact on C-Kit kinase in human cell lines and established the therapeutic impact of the engineered compound in a novel GIST mouse model, revealing a marked reduction of cardiotoxicity. These findings identify the reengineered imatinib as an agent to treat GISTs with curbed side effects and reveal a bottom-up approach to control drug specificity.

Cardiotoxicity induced by tyrosine kinase inhibitors

“…If it protects cardiomyocytes from oxidant stress, then its inhibition by imatinib explains its toxic effect. Recently, a modification to the molecule of imatinib to include an additional target, JNK, led to significant reduction of cardiotoxicity without any negative effect in the drug's potency [15]. This reengineered molecule, WBZ_4 is a methylated variant of imatinib.…”

Rapidly progressive dyspnea in gastrointestinal stromal tumor (GIST) with imatinib cardiac toxicity

“…Incidence of cardiotoxicity was cited as similar to onset of heart failure incidence in the general population, estimated at 0.2% per year, as evidenced by new-onset heart failure or left ventricular dysfunction [5]. While the impact of imatinib cardiotoxicity for GIST has been debated, molecular re-engineering of anticancer C-kit kinase inhibitors and cellular data on mitochondrial dysfunction and adenosine triphosphate (ATP) production deficit in murine models suggest a relationship, despite advocates for imatinib safety [11–14]. Prospective data on cardiac function and long-term follow-up data are needed to confirm murine observation in humans.…”

WaterMap originates in dehydron-based drug design

“…As noted in 2007 [4], labile hydration patterns in the target protein provide suitable "epistructural" (around the structure) blueprints. Thus, it has been shown that water becomes easily removable when found in the vicinity of certain packing defects in proteins known as dehydrons [1].…”

“…Lead optimization has been increasingly influenced by the identification of labile water molecules at the interface with the target protein [4][5][6][7]. These molecules are expected to be displaced upon drug binding.…”

“…The emerging design principle resulting from this simple observation was originally introduced in 2007 [4] in what constitutes a precursor to the WaterMap® software (Schrödinger, Inc.) [5,7]. Thus, the maps of "local de-wetting propensities" scanning the protein interface are regarded as epistructural blueprints for drug discovery [4,6], and in fact provide the guidance and inspiration to Water Map computations. The latter estimate the free energy cost associated with the transferring of water molecules from the protein interface to bulk solvent [7].…”