Dataset Information

Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

ABSTRACT: Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. Further optimization of 9 led to 12 with improved cellular activity, suitable pharmacokinetic profiles, and good in vivo efficacy in the mouse A549 xenograft model. Moreover, 12 displayed excellent selectivity over 95 kinases, indicating the contribution of its unusual flipped-peptide conformation to its selectivity.

SUBMITTER: Kusakabe K

PROVIDER: S-EPMC4025729 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

Kusakabe Ken-Ichi K Ide Nobuyuki N Daigo Yataro Y Itoh Takeshi T Higashino Kenichi K Okano Yousuke Y Tadano Genta G Tachibana Yuki Y Sato Yuji Y Inoue Makiko M Wada Tooru T Iguchi Motofumi M Kanazawa Takayuki T Ishioka Yukichi Y Dohi Keiji K Tagashira Sachie S Kido Yasuto Y Sakamoto Shingo S Yasuo Kazuya K Maeda Masahiro M Yamamoto Takahiko T Higaki Masayo M Endoh Takeshi T Ueda Kazuo K Shiota Takeshi T Murai Hitoshi H Nakamura Yusuke Y

ACS medicinal chemistry letters 20120606 7

Monopolar spindle 1 (Mps1) is an attractive cancer drug target due to the important role that it plays in centrosome duplication, the spindle assembly checkpoint, and the maintenance of chromosomal stability. A design based on JNK inhibitors with an aminopyridine scaffold and subsequent modifications identified diaminopyridine 9 with an IC50 of 37 nM. The X-ray structure of 9 revealed that the Cys604 carbonyl group of the hinge region flips to form a hydrogen bond with the aniline NH group in 9. ...[more]

PMID: 24900510

Similar Datasets

Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), toÂ cells treated with ND-2158 for the indicated times (Cy5).

Dataset Information

Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

Publications

Diaminopyridine-based potent and selective mps1 kinase inhibitors binding to an unusual flipped-Peptide conformation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets