Identification and Characterization of New Chemical Entities Targeting Apurinic/Apyrimidinic Endonuclease 1 for the Prevention of Chemotherapy-Induced Peripheral Neuropathy.
Chemotherapy-induced peripheral neuropathy (CIPN) is a potentially debilitating side effect of a number of chemotherapeutic agents. There are currently no U.S. Food and Drug Administration-approved interventions or prevention strategies for CIPN. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage caused by anticancer therapies could contribute to the neuropathy. DNA damage in sensory neurons after chemotherapy correlates with symptoms of CIPN. Augmenting apurinic/apyrimidinic endonuclease (APE)-1 function in the base excision repair pathway reverses this damage and the neurotoxicity caused by anticancer therapies. This neuronal protection is accomplished by either overexpressing APE1 or by using a first-generation targeted APE1 small molecule, E3330 [(2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]-undecanoic acid; also called APX3330]. Although E3330 has been approved for phase 1 clinical trials (Investigational New Drug application number IND125360), we synthesized novel, second-generation APE1-targeted molecules and determined whether they would be protective against neurotoxicity induced by cisplatin or oxaliplatin while not diminishing the platins' antitumor effect. We measured various endpoints of neurotoxicity using our ex vivo model of sensory neurons in culture, and we determined that APX2009 [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] is an effective small molecule that is neuroprotective against cisplatin and oxaliplatin-induced toxicity. APX2009 also demonstrated a strong tumor cell killing effect in tumor cells and the enhanced tumor cell killing was further substantiated in a more robust three-dimensional pancreatic tumor model. Together, these data suggest that the second-generation compound APX2009 is effective in preventing or reversing platinum-induced CIPN while not affecting the anticancer activity of platins.
Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.R.K., J.H.W., K.E.P., B.J.B., R.W., M.L.F.), and Department of Pharmacology and Toxicology (M.R.K., C.G., K.E.P.,M.L.F., M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and ApeX Therapeutics, Indianapolis, Indiana (J.H.W.) mkelley@iupui.edu.
Mark R
MR
Kelley
Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.R.K., J.H.W., K.E.P., B.J.B., R.W., M.L.F.), and Department of Pharmacology and Toxicology (M.R.K., C.G., K.E.P.,M.L.F., M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and ApeX Therapeutics, Indianapolis, Indiana (J.H.W.).
James H
JH
Wikel
Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.R.K., J.H.W., K.E.P., B.J.B., R.W., M.L.F.), and Department of Pharmacology and Toxicology (M.R.K., C.G., K.E.P.,M.L.F., M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and ApeX Therapeutics, Indianapolis, Indiana (J.H.W.).
Chunlu
C
Guo
Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.R.K., J.H.W., K.E.P., B.J.B., R.W., M.L.F.), and Department of Pharmacology and Toxicology (M.R.K., C.G., K.E.P.,M.L.F., M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and ApeX Therapeutics, Indianapolis, Indiana (J.H.W.).
Karen E
KE
Pollok
Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.R.K., J.H.W., K.E.P., B.J.B., R.W., M.L.F.), and Department of Pharmacology and Toxicology (M.R.K., C.G., K.E.P.,M.L.F., M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and ApeX Therapeutics, Indianapolis, Indiana (J.H.W.).
Barbara J
BJ
Bailey
Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.R.K., J.H.W., K.E.P., B.J.B., R.W., M.L.F.), and Department of Pharmacology and Toxicology (M.R.K., C.G., K.E.P.,M.L.F., M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and ApeX Therapeutics, Indianapolis, Indiana (J.H.W.).
Randy
R
Wireman
Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.R.K., J.H.W., K.E.P., B.J.B., R.W., M.L.F.), and Department of Pharmacology and Toxicology (M.R.K., C.G., K.E.P.,M.L.F., M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and ApeX Therapeutics, Indianapolis, Indiana (J.H.W.).
Melissa L
ML
Fishel
Department of Pediatrics, Herman B Wells Center for Pediatric Research (M.R.K., J.H.W., K.E.P., B.J.B., R.W., M.L.F.), and Department of Pharmacology and Toxicology (M.R.K., C.G., K.E.P.,M.L.F., M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and ApeX Therapeutics, Indianapolis, Indiana (J.H.W.).
Michael R
MR
Vasko
D000970:Antineoplastic Agents / Q000009:adverse effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004249:DNA Damage; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009944:Organoplatinum Compounds / Q000009:adverse effects; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000473:pathology
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003577:Cytochrome P-450 Enzyme System; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D002945:Cisplatin