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Berkeley, CA, United States

Plexxikon is an American drug-discovery company based in Berkeley, California, that was co-founded in 2001 by Joseph Schlessinger of Yale University with Sung-Hou Kim of the University of California, Berkeley.It uses a proprietary structural biology-based platform called Scaffold-Based Drug Discovery to build a pipeline of products in multiple therapeutic areas. This discovery process integrates multiple state-of-the-art technologies, including structural screening as one key component that it hopes will give a significant competitive advantage over other approaches. To date, the company has discovered several clinical and preclinical stage compounds. One of the most advanced drugs under development is an inhibitor of an activated form of the B-Raf kinase. A V600E mutant of the B-Raf kinase is found in approximately 70% of malignant melanomas, a large percentage of colorectal and thyroid cancers and many other tumor types. PLX4032 selectively inhibits this form of the kinase, and is currently in clinical trials. Plexxikon has entered into a partnership with Roche Pharmaceuticals to develop PLX4032 as a targeted anti-cancer therapeutic, which has shown particular promise for treating melanoma. Plexxikon is also collaborating with Wyeth Pharmaceuticals on several products for use in type II diabetes and other metabolic disorders. The most advanced of these agents is PLX204, which is currently in Phase 2 clinical trials for type II diabetes.In April 2011, Plexxikon was acquired by the Japanese pharmaceutical company Daiichi Sankyo for $805 million and an additional $130 m in potential milestone payments. Wikipedia.


Poulikakos P.I.,Sloan Kettering Cancer Center | Zhang C.,Howard Hughes Medical Institute | Bollag G.,Plexxikon | Shokat K.M.,Howard Hughes Medical Institute | Rosen N.,Sloan Kettering Cancer Center
Nature | Year: 2010

Tumours with mutant BRAF are dependent on the RAFĝ€" MEKĝ€"ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAFĝ€"CRAF) or heterodimers (CRAFĝ€"BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS. © 2010 Macmillan Publishers Limited. All rights reserved. Source


Patent
Plexxikon | Date: 2014-03-14

Heterocyclic compounds of formula (I), methods for their preparation, pharmaceutical compositions containing such a compound and their therapeutic uses.


Patent
Plexxikon | Date: 2015-09-10

Heterocyclic compounds of formula (I), pharmaceutical compositions containing such a compound and their therapeutic uses.


Compounds active on the receptor protein tyrosine kinases c-kit and/or c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or conditions and/or c-fms-mediated diseases or conditions, and methods for the use thereof.


Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

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