TY - JOUR
T1 - Novel derivatives of anaplastic lymphoma kinase inhibitors
T2 - Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib
AU - Radaram, Bhasker
AU - Pisaneschi, Federica
AU - Rao, Yi
AU - Yang, Ping
AU - Piwnica-Worms, David
AU - Alauddin, Mian M.
N1 - Funding Information:
The authors thank Dr. Seth T. Gammon for editing the figures and for providing helpful discussion. The authors also thank Kathryn Hale and Joe Munch in Scientific Publication Services in the Research Medical Library at MD Anderson for editing the manuscript. This work was supported by the U.S. National Institutes of Health through the Washington University?MD Anderson Cancer Center Inter-Institutional Molecular Imaging Center Grant (NCI P50 CA94056; DP-W) and through MD Anderson's Cancer Center Support Grant (P30CA016672), which supports the NMR Facility and Small Animal Imaging Facility used in the study; and by an MD Anderson Cancer Center Institutional Research Grant (MMA).
Funding Information:
The authors thank Dr. Seth T. Gammon for editing the figures and for providing helpful discussion. The authors also thank Kathryn Hale and Joe Munch in Scientific Publication Services in the Research Medical Library at MD Anderson for editing the manuscript. This work was supported by the U.S. National Institutes of Health through the Washington University − MD Anderson Cancer Center Inter-Institutional Molecular Imaging Center Grant ( NCI P50 CA94056 ; DP-W) and through MD Anderson’s Cancer Center Support Grant ( P30CA016672 ), which supports the NMR Facility and Small Animal Imaging Facility used in the study; and by an MD Anderson Cancer Center Institutional Research Grant (MMA).
Publisher Copyright:
© 2019 Elsevier Masson SAS
PY - 2019/11/15
Y1 - 2019/11/15
N2 - Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.
AB - Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases.
KW - Anaplastic lymphoma kinase
KW - Brain metastasis
KW - Lung cancer
KW - PET
KW - Targeted therapeutics
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U2 - 10.1016/j.ejmech.2019.111571
DO - 10.1016/j.ejmech.2019.111571
M3 - Article
C2 - 31425908
AN - SCOPUS:85070683533
SN - 0223-5234
VL - 182
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 111571
ER -