A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity. Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: Kusakabe, Ken-ichi; Ide, Nobuyuki; Daigo, Yataro; Itoh, Takeshi; Yamamoto, Takahiko; Kojima, Eiichi; Mitsuoka, Yasunori; Tadano, Genta; Tagashira, Sachie; Higashino, Kenichi; Okano, Yousuke; Sato, Yuji; Inoue, Makiko; Iguchi, Motofumi; Kanazawa, Takayuki; Ishioka, Yukichi; Dohi, Keiji; Kido, Yasuto; Sakamoto, Shingo; Ando, Shigeru; Maeda, Masahiro; Higaki, Masayo; Yoshizawa, Hidenori; Murai, Hitoshi; Nakamura, Yusuke
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 9(2015)
• Page Start: 2247
• Page End: 2260
• Publication Date: 2015-05-01
• Subjects: COT mitogen-activated protein kinase kinase kinase 8 -- DIEA N, N-diisopropylethylamine -- EtOAc ethyl acetate -- FLT3 fms-like tyrosine kinase 3 -- HATU 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxid hexafluorophosphate -- MeCN acetonitrile -- Mps1 monopolar spindle 1 -- MOS v-mos Moloney murine sarcoma viral oncogene homolog -- PASK per-arnt-sim (PAS) domain kinase -- PBK PDZ binding kinase -- PdCl2(dtbpf) [1, 1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) -- RP-HPLC reversed-phase high-performance liquid chromatography -- SNRK SNF related kinase -- TSSK2 testis-specific serine kinase 2 -- Xantphos 4, 5-bis(diphenylphosphino)-9, 9-dimethylxanthene; Monopolar spindle 1 -- Mps1 -- TTK -- Kinase -- Inhibitor -- Peptide flip -- Flipped peptide -- Cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.02.042
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC50 = 5.3 nM, A549 IC50 = 26 nM). A clear correlation between cellular Mps1 and antiproliferative IC50 values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of19c, a deamino analogue33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region.