2X9E

HUMAN MPS1 IN COMPLEX WITH NMS-P715

Summary for 2X9E

• Entry DOI: 10.2210/pdb2x9e/pdb
• Related: 2ZMC 2ZMD 3CEK 3DBQ 3GFW 3H9F 3HMN 3HMO 3HMP
• Descriptor: DUAL SPECIFICITY PROTEIN KINASE TTK, N-(2,6-DIETHYLPHENYL)-1-METHYL-8-({4-[(1-METHYLPIPERIDIN-4-YL)CARBAMOYL]-2-(TRIFLUOROMETHOXY)PHENYL}AMINO)-4,5-DIHYDRO-1H-PYRAZOLO[4,3-H]QUINAZOLINE-3-CARBOXAMIDE (3 entities in total)
• Functional Keywords: kinase, serine/threonine-protein kinase, transferase, tyrosine-protein kinase, mitotic checkpoint
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 36916.38

Authors

Colombo, R.,Caldarelli, M.,Mennecozzi, M.,Giorgini, M.L.,Sola, F.,Cappella, P.,Perrera, C.,DePaolini, S.R.,Rusconi, L.,Cucchi, U.,Avanzi, N.,Bertrand, J.A.,Bossi, R.T.,Pesenti, E.,Galvani, A.,Isacchi, A.,Colotta, F.,Donati, D.,Moll, J. (deposition date: 2010-03-17, release date: 2010-12-29, Last modification date: 2023-12-20)

Primary citation

Colombo, R.,Caldarelli, M.,Mennecozzi, M.,Giorgini, M.L.,Sola, F.,Cappella, P.,Perrera, C.,Depaolini, S.R.,Rusconi, L.,Cucchi, U.,Avanzi, N.,Bertrand, J.A.,Bossi, R.T.,Pesenti, E.,Galvani, A.,Isacchi, A.,Colotta, F.,Donati, D.,Moll, J.
Targeting the Mitotic Checkpoint for Cancer Therapy with Nms-P715, an Inhibitor of Mps1 Kinase.
Cancer Res., 70:10255-, 2010

PubMed Abstract: MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells.

PubMed: 21159646
DOI: 10.1158/0008-5472.CAN-10-2101

Experimental method

X-RAY DIFFRACTION (3.1 Å)