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Namboodiri H.V.,Locus Pharmaceuticals | Bukhtiyarova M.,Locus Pharmaceuticals | Ramcharan J.,Locus Pharmaceuticals | Karpusas M.,Locus Pharmaceuticals | And 4 more authors.
Biochemistry | Year: 2010

Protein kinases c-Abl, b-Raf, and p38α are recognized as important targets for therapeutic intervention. c-Abl and b-Raf are major targets of marketed oncology drugs Imatinib (Gleevec) and Sorafenib (Nexavar), respectively, and BIRB-796 is a p38α inhibitor that reached Phase II clinical trials. A shared feature of these drugs is the fact that they bind to the DFG-out forms of their kinase targets. Although the discovery of this class of kinase inhibitors has increased the level of emphasis on the design of DFG-out inhibitors, the structural determinants for their binding and stabilization of the DFG-out conformation remain unclear. To improve our understanding of these determinants, we determined cocrystal structures of Imatinib and Sorafenib with p38α. We also conducted a detailed analysis of Imatinib and Sorafenib binding to p38α in comparison with BIRB-796, including binding kinetics, binding interactions, the solvent accessible surface area (SASA) of the ligands, and stabilization of key structural elements of the protein upon ligand binding. Our results yield an improved understanding of the structural requirements for stabilizing the DFG-out form and a rationale for understanding the genesis of ligand selectivity among DFG-out inhibitors of protein kinases. © 2010 American Chemical Society.


Protein kinases c-Abl, b-Raf, and p38alpha are recognized as important targets for therapeutic intervention. c-Abl and b-Raf are major targets of marketed oncology drugs Imatinib (Gleevec) and Sorafenib (Nexavar), respectively, and BIRB-796 is a p38alpha inhibitor that reached Phase II clinical trials. A shared feature of these drugs is the fact that they bind to the DFG-out forms of their kinase targets. Although the discovery of this class of kinase inhibitors has increased the level of emphasis on the design of DFG-out inhibitors, the structural determinants for their binding and stabilization of the DFG-out conformation remain unclear. To improve our understanding of these determinants, we determined cocrystal structures of Imatinib and Sorafenib with p38alpha. We also conducted a detailed analysis of Imatinib and Sorafenib binding to p38alpha in comparison with BIRB-796, including binding kinetics, binding interactions, the solvent accessible surface area (SASA) of the ligands, and stabilization of key structural elements of the protein upon ligand binding. Our results yield an improved understanding of the structural requirements for stabilizing the DFG-out form and a rationale for understanding the genesis of ligand selectivity among DFG-out inhibitors of protein kinases.


Patent
Locus Pharmaceuticals | Date: 2010-04-28

A compound of formula (I): wherein all symbols have the same meanings as defined in the specification; a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof, has a Btk inhibitory activity, and is useful as a method for preventing and/or treating a rheumatoid arthritis, an autoimmune disease, a B cell lymphoma of cancer, and the like.


Patent
Locus Pharmaceuticals | Date: 2012-02-29

A compound of formula (I): wherein all symbols have the same meanings as defined in the specification; a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof, has an Itk inhibitory activity, and is useful as a method for preventing and/or treating atopic dermatitis, and the like.


Locus Pharmaceuticals | Entity website

Buy Janumet or Janumet Generic sitagliptin and metformin hydrochloride Janumet Common Uses The generic name of Janumet is sitagliptin and metformin hydrochloride. It is used for the treatment of adults with type 2 diabetes ...


Locus Pharmaceuticals | Entity website

Buy Crestor or Crestor Generic rosuvastatin Crestor Common Uses The generic name of Crestor is rosuvastatin. It is categorized under a group of medicines called statins or HMG CoA reductase inhibitors ...


NEW YORK--(BUSINESS WIRE)--Tyme, Inc. (OTC QB:TYMI), a research and development company focused on developing drug candidates for the treatment of cancer, has appointed Robert Dickey IV to serve as its Chief Financial Officer (CFO). Most recently CFO of NeoStem, Inc. Mr. Dickey is a life sciences industry veteran and former investment banker with C-level and senior leadership experience in public, private, revenue stage, development stage and start-up companies. Mr. Dickey will report to Steve Hoffman, Chief Executive Officer of Tyme, Inc. “We are extremely pleased to welcome Rob to the Tyme executive team,” said CEO Steve Hoffman. “This is a pivotal and exciting stage in our company’s growth and Rob’s strong track record makes him an ideal fit for our organization as we implement our plans to grow and increase shareholder value.” Mr. Dickey added, “Joining Tyme as CFO at this important stage of its operational development is very exciting. I believe Tyme has tremendous potential to become a major player in oncology and I look forward to joining this team as we grow.” Mr. Dickey has more than 30 years of industry and financial experience. Prior to joining Tyme, he served as CFO for NeoStem, a publicly-traded, revenue stage regenerative medicine company, principally focused on therapies involving adult stem cells. He also previously served as Senior Vice President at Hemispherx Biopharma, Inc., a publicly-traded company involved in immune-modulatory therapies and Senior Vice President, Chief Financial Officer and Business Unit Manager at StemCyte, Inc., an umbilical cord stem cell therapeutics company. Other management experience includes leadership positions at Protarga, Inc., a company developing cancer therapies, and Locus Pharmaceuticals, a company involved in computational drug design. Prior to his experience in the life sciences industry, he spent 18 years as an investment banker, 14 of those at Lehman Brothers, with a background split between M&A and capital markets transactions across a variety of industries. Mr. Dickey holds an M.B.A from The Wharton School, University of Pennsylvania, and an A.B. from Princeton University. He currently also serves on the Board of Directors for Sanuthera, Inc., a venture-backed medical device company with an advanced stage therapy for tinnitus. Tyme is a pharmaceutical company focused on discovering and developing highly targeted cancer therapeutics for a broad range of oncology indications. Tyme is the originator of what it believes to be a novel, proprietary treatment regimen consisting of a rationally-designed combination of therapeutic agents aimed at exploiting the aberrant metabolic characteristics of cancer cells as well as activating the endogenous immune response against tumors. Tyme's approach is hypothesized to permit selective elimination of cancer cells, while simultaneously improving patients' well-being, particularly with respect to pain severity and functional independence. Tyme is currently developing for use in humans SM-88, a proprietary compound, which the company believes to be a first-in-class drug that harnesses the body’s own immune defenses to fight tumor cells. SM-88 is a novel combination drug that synergistically target the unique metabolic features of cancer cells, thus providing a selective method of altering the susceptibility of cancer cells to oxidative stress. Tyme has completed a proof-of-concept clinical study for SM-88 in late-stage cancer patients with relapsed or highly refractory disease and is working towards submitting an Investigational New Drug (IND) application to the U.S. Food and Drug Administration, with the goal of beginning a randomized clinical trial in multiple U.S. centers in the near future. Tyme anticipates an IND submission to the FDA in mid-2015. For more information, visit our website: www.tymetechnologiesinc.com. This press release contains forward-looking statements. These statements involve known and unknown risks, uncertainties and other factors which may cause the company’s actual results, performance or achievements to be materially different from any historical results and future results, performances or achievements expressed or implied by the forward-looking statements. These risks and uncertainties include, but are not limited to, the factors described in the section captioned "Risk Factors" of Tyme's Current Report on Form 8-K/A filed with the US Securities and Exchange Commission on April 16, 2015 (available at www.sec.gov). Readers can identify forward-looking statements by terms such as "anticipates," "believes," "could," "estimates," "expects," "intends," "may," "plans," "potential," "predicts," "projects," "should," "would" and similar expressions intended to identify forward-looking statements, and forward-looking statements within this press release include statements regarding our drug development strategies, clinical trials and plans for submitting an IND with the FDA. Forward-looking statements reflect Tyme Technologies' current views with respect to future events and are based on assumptions and subject to risks and uncertainties. Given these uncertainties, readers should not place undue reliance on these forward-looking statements.


PubMed | Locus Pharmaceuticals
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2015

Fragment-based drug design (FBDD) has become an important component of the drug discovery process. The use of fragments can accelerate both the search for a hit molecule and the development of that hit into a lead molecule for clinical testing. In addition to experimental methodologies for FBDD such as NMR and X-ray Crystallography screens, computational techniques are playing an increasingly important role. The success of the computational simulations is due in large part to how the database of virtual fragments is prepared. In order to prepare the fragments appropriately it is necessary to understand how FBDD differs from other approaches and the issues inherent in building up molecules from smaller fragment pieces. The ultimate goal of these calculations is to link two or more simulated fragments into a molecule that has an experimental binding affinity consistent with the additive predicted binding affinities of the virtual fragments. Computationally predicting binding affinities is a complex process, with many opportunities for introducing error. Therefore, care should be taken with the fragment preparation procedure to avoid introducing additional inaccuracies.This chapter is focused on the preparation process used to create a virtual fragment database. Several key issues of fragment preparation which affect the accuracy of binding affinity predictions are discussed. The first issue is the selection of the two-dimensional atomic structure of the virtual fragment. Although the particular usage of the fragment can affect this choice (i.e., whether the fragment will be used for calibration, binding site characterization, hit identification, or lead optimization), general factors such as synthetic accessibility, size, and flexibility are major considerations in selecting the 2D structure. Other aspects of preparing the virtual fragments for simulation are the generation of three-dimensional conformations and the assignment of the associated atomic point charges.


PubMed | Locus Pharmaceuticals
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2015

One of the most powerful tools for designing drug molecules is an understanding of the target proteins binding site. Identifying key amino acids and understanding the electronic, steric, and solvation properties of the site enables the design of potent ligands. Of equal importance for the success of a drug discovery program is the evaluation of binding site druggability. Determining, a priori, if a particular binding site has the appropriate character to bind drug-like ligands saves research time and money.While there are a variety of experimental and computational techniques to identify and characterize binding sites, the focus of this chapter is on Binding Site Analysis (BSA) using virtual fragment simulations. The methodology of the technique is described, along with examples of successful application to drug discovery programs. BSA both indicates if a protein is a viable target for drug discovery and provides a roadmap for designing ligands. Using a computational fragment-based method is a effective means of understanding of a binding site.

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