Fragment-Based Ligand Design of Novel Potent Inhibitors of Tankyrases

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• 作者：E. Andreas Larsson ; Anna Jansson ; Fui Mee Ng ; Siew Wen Then ; Resmi Panicker ; Boping Liu ; Kanda Sangthongpitag ; Vishal Pendharkar ; Shi Jing Tai ; Jeffrey Hill ; Chen Dan ; Soo Yei Ho ; Wei Wen Cheong ; Anders Poulsen ; Stephanie Blanchard ; Grace Ruiting Lin ; Jenefer Alam ; Thomas H. Keller ; P盲r Nordlund
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4497-4508
• 全文大小：514K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC₅₀ values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.