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Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

Bioorganic & medicinal chemistry (2014-07-22)
Radoslaw Laufer, Grace Ng, Yong Liu, Narendra Kumar B Patel, Louise G Edwards, Yunhui Lang, Sze-Wan Li, Miklos Feher, Don E Awrey, Genie Leung, Irina Beletskaya, Olga Plotnikova, Jacqueline M Mason, Richard Hodgson, Xin Wei, Guodong Mao, Xunyi Luo, Ping Huang, Erin Green, Reza Kiarash, Dan Chi-Chia Lin, Marees Harris-Brandts, Fuqiang Ban, Vincent Nadeem, Tak W Mak, Guohua J Pan, Wei Qiu, Nickolay Y Chirgadze, Henry W Pauls
ABSTRACT

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Nocodazole, ≥99% (TLC), powder
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, ≥99%
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, ≥98% (TLC)
Sigma-Aldrich
Sulforhodamine B, Dye content 75 %
Sigma-Aldrich
Sulforhodamine B sodium salt, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
α-Methoxyphenylacetic acid, 99%
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, ≥98.0% (NT)
Sigma-Aldrich
(±)-α-Methoxyphenylacetic acid, crystalline
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine, tablet, 1 mg substrate per tablet
Sigma-Aldrich
2-Thiopheneethanol, 98%
Sigma-Aldrich
Sulforhodamine B sodium salt, Technical grade
Sigma-Aldrich
2-Thiopheneacetyl chloride, 98%
Sigma-Aldrich
2-Thiophenesulfonyl chloride, 96%
Sigma-Aldrich
β-D-Allose, rare aldohexose sugar
Sigma-Aldrich
(R)-(−)-α-Methoxyphenylacetic acid, 99%
Sigma-Aldrich
(S)-(+)-α-Methoxyphenylacetic acid, 99%
Supelco
3,3′,5,5′-Tetramethylbenzidine, standard for GC
Sigma-Aldrich
1H-Indazole-6-carboxylic acid, 97%
Sigma-Aldrich
benzenesulfonamide-3-boronic acid pinacol ester, AldrichCPR
Sigma-Aldrich
4-sulfamoylphenylboronic acid, pinacol ester, AldrichCPR
Sigma-Aldrich
1-Phenyl-1-cyclopropanecarboxylic acid, 97%
Sigma-Aldrich
Cyclopentylphenylacetic acid, 97%
Supelco
(R)-(−)-α-Methoxyphenylacetic acid, for chiral derivatization, LiChropur, ≥99.0%