Structural Basis and SAR for G007-LK, a Lead Stage 1,2,4-Triazole Based Specific Tankyrase 1/2 Inhibitor

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• 作者：Andrew Voronkov ; Daniel D. Holsworth ; Jo Waaler ; Steven R. Wilson ; Bie Ekblad ; Harmonie Perdreau-Dahl ; Huyen Dinh ; Gerard Drewes ; Carsten Hopf ; Jens P. Morth ; Stefan Krauss
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：3012-3023
• 全文大小：694K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure鈥揳ctivity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chemical analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, 鈥渞ule of 5鈥?compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochemical IC₅₀ values of 46 nM and 25 nM, respectively, and a cellular IC₅₀ value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystallized with 66, and the X-ray structure was determined at 2.8 脜 resolution in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compound鈥檚 high target selectivity and specificity. Our study provides a significantly optimized compound for targeting TNKS1/2 in vitro and in vivo.