An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic.
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.
Fernández
Ariel
A
Department of Bioengineering and Applied Physics Division, Rice Quantum Institute, Rice University, Houston, Texas 77005, USA. arifer@rice.edu
Sanguino
Angela
A
Peng
Zhenghong
Z
Ozturk
Eylem
E
Chen
Jianping
J
Crespo
Alejandro
A
Wulf
Sarah
S
Shavrin
Aleksander
A
Qin
Chaoping
C
Ma
Jianpeng
J
Trent
Jonathan
J
Lin
Yvonne
Y
Han
Hee-Dong
HD
Mangala
Lingegowda S
LS
Bankson
James A
JA
Gelovani
Juri
J
Samarel
Allen
A
Bornmann
William
W
Sood
Anil K
AK
Lopez-Berestein
Gabriel
G
D000818:Animals; D001549:Benzamides; D054715:Cardiotoxins / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology*; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology; D010879:Piperazines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D054715:Cardiotoxins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl; D048670:MAP Kinase Kinase 4