cas 639090-55-4, Yclopropanecarboxylic acid N-[4-[[4-chloro-6-(5-methyl-2H-pyrazol-3-ylamino)pyrimidin-2-yl]sulfanyl]phenyl]amide

Articles about 639090-55-4Total 14 be found

PYRIMIDINE DERIVATIVES AS TROPOMYOSIN RECEPTOR KINASE A (TRKA) INHIBITORS
The present invention relates to novel TrkA inhibitors ofofmrula (1) which are useful in the treatment or prevention of acute and chronic pain but also for other abnormal activities of TrkA beyond pain therapy, such as inflammation and cancer.
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Page/Page column 21-22

(2019/06/11)

From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical Candidate
Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compounds in clinical trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, toward the pain target TrkA. First, selectivity-determining features in binding pockets were identified by fusing interaction grids of several key and off-target conformations. A focused library was subsequently created and prioritized using a multiobjective selection scheme that filters for selective and highly active compounds based on orthogonal methods grounded in computational chemistry and machine learning. Eighteen high-ranking compounds were synthesized and experimentally tested. The top-ranked compound has 10000-fold improved selectivity versus AurA, nanomolar cellular activity, and is highly selective in a kinase panel. This was achieved in a single round of automated in silico optimization, highlighting the power of recent advances in computer-aided drug design to automate design and selection processes.
Turk, Samo,Merget, Benjamin,Eid, Sameh,Fulle, Simone
p. 4851 - 4859
(2018/05/23)

Tozasertib Analogues as Inhibitors of Necroptotic Cell Death
Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that target the active site of RIPK1. Tozasertib, a type I pan-aurora kinase (AurK) inhibitor, was found to show a very high affinity for RIPK1. Because tozasertib presents the typical structural elements of a type I kinase inhibitor, the development of structural analogues of tozasertib is a good starting point for identifying novel type I RIPK1 inhibitors. In this paper, we identified interesting inhibitors of mTNF-induced necroptosis with no significant effect on AurK A and B, resulting in no nuclear abnormalities as is the case for tozasertib. Compounds 71 and 72 outperformed tozasertib in an in vivo TNF-induced systemic inflammatory response syndrome (SIRS) mouse model.
Hofmans, Sam,Devisscher, Lars,Martens, Sofie,Van Rompaey, Dries,Goossens, Kenneth,Divert, Tatyana,Nerinckx, Wim,Takahashi, Nozomi,De Winter, Hans,Van Der Veken, Pieter,Goossens, Vera,Vandenabeele, Peter,Augustyns, Koen
p. 1895 - 1920
(2018/03/21)

As inhibitors of Aurora kinases substituted pyrimidine derivatives
The present invention relates to a substituted and aurora kinase-inhibiting pyrimidine derivative as represented by formula (I) or (Ia), tautomer, hydrate, solvate, ester or pharmaceutically acceptable salt thereof, and pharmaceutical composition comprising the compounds as active ingredients, as well as uses of the compounds and the pharmaceutical composition thereof in the preparation of drugs for protecting against, treating, curing or alleviating proliferative diseases of a patient.
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Paragraph 0333; 0334

(2016/10/09)

Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
supporting information
p. 8551 - 8556
(2013/09/12)

The discovery of the potent aurora inhibitor MK-0457 (VX-680)
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) containing the T315I mutation.
Bebbington, David,Binch, Hayley,Charrier, Jean-Damien,Everitt, Simon,Fraysse, Damien,Golec, Julian,Kay, David,Knegtel, Ronald,Mak, Chau,Mazzei, Francesca,Miller, Andrew,Mortimore, Michael,O'Donnell, Michael,Patel, Sanjay,Pierard, Francoise,Pinder, Joanne,Pollard, John,Ramaya, Sharn,Robinson, Daniel,Rutherford, Alistair,Studley, John,Westcott, James
scheme or table
p. 3586 - 3592
(2010/03/31)

AURORA INHIBITORS CONTAINING A ZINC BINDING MOIETY
The present invention relates to Aurora inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 56; 57

(2009/08/14)

Kinase inhibition and anticancer therapy
This invention relates to novel uses for Compound E in the treatment of diseases, in particular cancer, associated with aberrant kinase expression.
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(2009/05/29)

A NOVEL LACTIC ACID FORMULATION OF MK-0457 USEFUL FOR THE TREATMENT OF CANCER
A lactic acid formulation, and a process to prepare that formulation, of MK-0457 is disclosed:. Such a formulation is useful in the treatment of cancer.
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Page/Page column 7

(2008/06/13)

RET TYROSINE KINASE INHIBITION
The present invention provides methods for inhibiting RET tyrosine kinase. Further, the present invention also provides methods of treating or preventing thyroid cancer.
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Page/Page column 27

(2008/06/13)

JAK2 TYROSINE KINASE INHIBITION
The present invention provides methods for inhibiting JAK2 tyrosine kinase. Further, the present invention also provides methods of treating or preventing myeloproliferative disorders.
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Page/Page column 27

(2008/06/13)

COMBINATION CANCER THERAPY
The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of an Aurora kinase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, in a first trea
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(2008/06/13)