Abstract
Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET, and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly potent inhibitor of FLT3.
References
Dec 19, 1998·Annals of Hematology·V GatteiA Pinto
Apr 8, 1999·Leukemia & Lymphoma·H G DrexlerH Quentmeier
Aug 3, 2004·Nature Reviews. Drug Discovery·Ismail Kola, John Landis
Jul 26, 2008·The Journal of International Medical Research·Q ZengQ Zhang
Nov 26, 2008·Journal of Structural Biology·Xudong HuangSirano Dhe-Paganon
Apr 10, 2009·Blood·James W VardimanClara D Bloomfield
Jan 23, 2010·Nature Reviews. Cancer·Zachary A KnightKevan M Shokat
Dec 16, 2011·Future Medicinal Chemistry·Neil O CarragherDavid A Cameron
Mar 14, 2012·Journal of Medicinal Chemistry·Jonathan A LeeDaniel J Sall
Jun 5, 2012·ACS Medicinal Chemistry Letters·Jing LiuXiaodong Wang
May 8, 2013·Cancer Research·Andrea MorandiClare M Isacke
Sep 12, 2013·Nature Biotechnology·Cormac Sheridan
Jan 13, 2015·Expert Review of Hematology·Melanie JanningSonja Loges
May 15, 2015·The New England Journal of Medicine·Jerry Avorn
Jul 15, 2015·Leukemia·I-K ParkM A Caligiuri
Nov 12, 2015·Journal of Medicinal Chemistry·Samuel H MyersAsier Unciti-Broceta
Mar 2, 2016·Journal of Health Economics·Joseph A DiMasiRonald W Hansen
Apr 27, 2016·Journal of Medicinal Chemistry·Craig FraserAsier Unciti-Broceta
Jan 11, 2017·British Journal of Cancer·Carl M GayLauren Averett Byers
Mar 3, 2017·Current Oncology Reports·Marie Schoumacher, Mike Burbridge
Jul 21, 2017·The Journal of Biological Chemistry·Ketan S GajiwalaAl Stewart
Sep 13, 2017·Leukemia·K ReiterP A Greif
Citations
Jan 17, 2019·Future Oncology·Zhao-Shan NiuWen-Hong Wang
Jun 21, 2019·Current Topics in Medicinal Chemistry·Zhi-Gang SunYong Qian
Apr 22, 2020·Future Medicinal Chemistry·Lexian TongTao Liu
Aug 31, 2019·Bioorganic & Medicinal Chemistry Letters·Qiaoling XuYajing Liu
Jan 23, 2021·RSC Medicinal Chemistry·Daniel J Baillache, Asier Unciti-Broceta
Dec 24, 2019·ACS Omega·Olga Cruz-LópezAsier Unciti-Broceta
Jun 27, 2020·ACS Combinatorial Science·Ming-Shu WangWei Huang