Structure-guided design of anti-cancer ribonucleotide reductase inhibitors

被引:11
作者
Misko, Tessianna A. [1 ]
Liu, Yi-Ting [2 ]
Harris, Michael E. [3 ]
Oleinick, Nancy L. [4 ]
Pink, John [5 ]
Lee, Hsueh-Yun [2 ,6 ]
Dealwis, Chris G. [1 ,7 ]
机构
[1] Case Western Reserve Univ, Sch Med, Dept Pharmacol, 10900 Euclid Ave, Cleveland, OH 44106 USA
[2] Taipei Med Univ, Coll Pharm, Sch Pharm, 250 Wuxing St, Taipei 11031, Taiwan
[3] Univ Florida, Dept Chem, Gainesville, FL 32611 USA
[4] Case Western Reserve Univ, Sch Med, Dept Radiat Oncol, Cleveland, OH 44106 USA
[5] Case Western Reserve Univ, Case Comprehens Canc Ctr, Sch Med, Cleveland, OH 44106 USA
[6] Taipei Med Univ, Coll Pharm, PhD Program Biotechnol Res & Dev, Taipei, Taiwan
[7] Case Western Reserve Univ, Ctr Prote, Dept Chem, Cleveland, OH 44106 USA
关键词
Ribonucleotide reductase; cancer; inhibitor; pancreatic; phosphate-binding; ACCURATE DOCKING; DNA-REPLICATION; NITRIC-OXIDE; MECHANISM; GEMCITABINE; 2-CHLORO-9-(2-DEOXY-2-FLUORO-BETA-D-ARABINOFURANOSYL)ADENINE; METABOLISM; DAMAGE; GLIDE; 2'; 2'-DIFLUORO-2'-DEOXYCYTIDINE;
D O I
10.1080/14756366.2018.1545226
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ribonucleotide reductase (RR) catalyses the rate-limiting step of dNTP synthesis, establishing it as an important cancer target. While RR is traditionally inhibited by nucleoside-based antimetabolites, we recently discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH) that binds reversibly to the catalytic site (C-site). Here we report the synthesis and in vitro evaluation of 13 distinct compounds (TP1-13) with improved binding to hRR over NSAH (TP8), with lower K-D's and more predicted residue interactions. Moreover, TP6 displayed the greatest growth inhibiting effect in the Panc1 pancreatic cancer cell line with an IC50 of 0.393 mu M. This represents more than a 2-fold improvement over NSAH, making TP6 the most potent compound against pancreatic cancer emerging from the hydrazone inhibitors. NSAH was optimised by the addition of cyclic and polar groups replacing the naphthyl moiety, which occupies the phosphate-binding pocket in the C-site, establishing a new direction in inhibitor design.
引用
收藏
页码:438 / 450
页数:13
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