4728-12-5Relevant articles and documents
Schaeffer,Stevens
, p. 1241 (1973)
GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer
Liang, Jun,Zbieg, Jason R.,Blake, Robert A.,Chang, Jae H.,Daly, Stephen,Dipasquale, Antonio G.,Friedman, Lori S.,Gelzleichter, Thomas,Gill, Matthew,Giltnane, Jennifer M.,Goodacre, Simon,Guan, Jane,Hartman, Steven J.,Ingalla, Ellen Rei,Kategaya, Lorn,Kiefer, James R.,Kleinheinz, Tracy,Labadie, Sharada S.,Lai, Tommy,Li, Jun,Liao, Jiangpeng,Liu, Zhiguo,Mody, Vidhi,McLean, Neville,Metcalfe, Ciara,Nannini, Michelle A.,Oeh, Jason,O'Rourke, Martin G.,Ortwine, Daniel F.,Ran, Yingqing,Ray, Nicholas C.,Roussel, Fabien,Sambrone, Amy,Sampath, Deepak,Schutt, Leah K.,Vinogradova, Maia,Wai, John,Wang, Tao,Wertz, Ingrid E.,White, Jonathan R.,Yeap, Siew Kuen,Young, Amy,Zhang, Birong,Zheng, Xiaoping,Zhou, Wei,Zhong, Yu,Wang, Xiaojing
supporting information, p. 11841 - 11856 (2021/07/31)
Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.
Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs
?pa?ek, Petr,Keough, Dianne T.,Chavchich, Marina,Dra?ínsky, Martin,Janeba, Zlatko,Naesens, Lieve,Edstein, Michael D.,Guddat, Luke W.,Hocková, Dana
, p. 4008 - 4030 (2017/07/05)
Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower Ki values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest Ki values obtained for the two parasite enzymes were 0.1?μM (Pf) and 0.2?μM (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture with IC50 values of 0.8 and 1.5?μM. These two compounds exhibited low cytotoxicity in human A549 cells having CC50 values of >300?μM resulting in an excellent selectivity index.