title: A WEE1 Inhibitor Analog of AZD1775 Maintains Synergy with Cisplatin and Demonstrates Reduced Single-Agent Cytotoxicity in Medulloblastoma Cells.
abstract: The current treatment for medulloblastoma includes surgical resection, radiation, and cytotoxic chemotherapy. Although this approach has improved survival rates, the high doses of chemotherapy required for clinical efficacy often result in lasting neurocognitive defects and other adverse events. Therefore, the development of chemosensitizing agents that allow dose reductions of cytotoxic agents, limiting their adverse effects but maintaining their clinical efficacy, would be an attractive approach to treat medulloblastoma. We previously identified WEE1 kinase as a new molecular target for medulloblastoma from an integrated genomic analysis of gene expression and a kinome-wide siRNA screen of medulloblastoma cells and tissue. In addition, we demonstrated that WEE1 prevents DNA damage-induced cell death by cisplatin and that the WEE1 inhibitor AZD1775 displays synergistic activity with cisplatin. AZD1775 was developed as a WEE1 inhibitor from an initial hit from a high-throughput screen. However, given the lack of structure-activity data for AZD1775, we developed a small series of analogs to determine the requirements for WEE1 inhibition and further examine the effects of WEE1 inhibition in medulloblastoma. Interestingly, the compounds that inhibited WEE1 in the same nanomolar range as AZD1775 had significantly reduced single-agent cytotoxicity compared with AZD1775 and displayed synergistic activity with cisplatin in medulloblastoma cells. The potent cytotoxicity of AZD1775, unrelated to WEE1 inhibition, may result in dose-limiting toxicities and exacerbate adverse effects; therefore, WEE1 inhibitors that demonstrate low cytotoxicity could be dosed at higher concentrations to chemosensitize the tumor and potentiate the effect of DNA-damaging agents such as cisplatin.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , 12850 East Montview Boulevard, V20-2102, Aurora, Colorado 80045, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Matheson
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Anschutz Medical Campus , 12800 E 19th Ave, Mail Stop 8302, Aurora, Colorado 80045, United States.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Anschutz Medical Campus , 12800 E 19th Ave, Mail Stop 8302, Aurora, Colorado 80045, United States.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Amani
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Anschutz Medical Campus , 12800 E 19th Ave, Mail Stop 8302, Aurora, Colorado 80045, United States.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Harris
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , 12850 East Montview Boulevard, V20-2102, Aurora, Colorado 80045, United States.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Backos
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Anschutz Medical Campus , 12800 E 19th Ave, Mail Stop 8302, Aurora, Colorado 80045, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Donson
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , 12850 East Montview Boulevard, V20-2102, Aurora, Colorado 80045, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Anschutz Medical Campus , 12800 E 19th Ave, Mail Stop 8302, Aurora, Colorado 80045, United States.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.affiliation: Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Anschutz Medical Campus , 12800 E 19th Ave, Mail Stop 8302, Aurora, Colorado 80045, United States.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , 12850 East Montview Boulevard, V20-2102, Aurora, Colorado 80045, United States.
authors.forename: Philip
authors.initials: P
authors.lastname: Reigan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib; D002945:Cisplatin