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Rauniyar N.,Scripps Research Institute | Gao B.,Proteostasis Therapeutics | McClatchy D.B.,Scripps Research Institute | Yates J.R.,Scripps Research Institute
Journal of Proteome Research | Year: 2013

Stable isotope labeling via isobaric derivatization of peptides is a universally applicable approach that enables concurrent identification and quantification of proteins in different samples using tandem mass spectrometry. In this study, we evaluated the performance of amine-reactive isobaric tandem mass tag (TMT), available as duplex and sixplex sets, with regard to their ability to elucidate protein expression changes. Using rat brain tissue from two different developmental time points, postnatal day 1 (p1) and 45 (p45), as a model system, we compared the protein expression ratios (p45/p1) observed using duplex TMT tags in triplicate measurements versus sixplex tag in a single LC-MS/MS analysis. A correlation of 0.79 in relative protein abundance was observed in the proteins quantified by these two sets of reagents. However, more proteins passed the criteria for significant fold change (-1.0 ≤ log 2 ratio (p45/p1) ≥ +1.0 and p < 0.05) in the sixplex analysis. Nevertheless, in both methods most proteins showing significant fold change were identified by multiple spectra, increasing their quantification precision. Additionally, the fold change in p45 rats against p1, observed in TMT experiments, was corroborated by a metabolic labeling strategy where relative quantification of differentially expressed proteins was obtained using 15N-labeled p45 rats as an internal standard. © 2012 American Chemical Society.

Kaufman R.J.,Sanford Burnham Institute for Medical Research | Malhotra J.D.,Proteostasis Therapeutics
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2014

Calcium homeostasis is central to all cellular functions and has been studied for decades. Calcium acts as a critical second messenger for both extracellular and intracellular signaling and is fundamental in cell life and death decisions (Berridge et al., 2000) [1]. The calcium gradient in the cell is coupled with an inherent ability of the divalent cation to reversibly bind multiple target biological molecules to generate an extremely versatile signaling system [2]. Calcium signals are used by the cell to control diverse processes such as development, neurotransmitter release, muscle contraction, metabolism, autophagy and cell death. "Cellular calcium overload" is detrimental to cellular health, resulting in massive activation of proteases and phospholipases leading to cell death (Pinton et al., 2008) [3]. Historically, cell death associated with calcium ion perturbations has been primarily recognized as necrosis. Recent evidence clearly associates changes in calcium ion concentrations with more sophisticated forms of cellular demise, including apoptosis (Kruman et al., 1998; Tombal et al., 1999; Lynch et al., 2000; Orrenius et al., 2003) [4-7]. Although the endoplasmic reticulum (ER) serves as the primary calcium store in the metazoan cell, dynamic calcium release to the cytosol, mitochondria, nuclei and other organelles orchestrate diverse coordinated responses. Most evidence supports that calcium transport from the ER to mitochondria plays a significant role in regulating cellular bioenergetics, production of reactive oxygen species, induction of autophagy and apoptosis. Recently, molecular identities that mediate calcium traffic between the ER and mitochondria have been discovered (Mallilankaraman et al., 2012a; Mallilankaraman et al., 2012b; Sancak et al., 2013)[8-10]. The next questions are how they are regulated for exquisite tight control of ER-mitochondrial calcium dynamics. This review attempts to summarize recent advances in the role of calcium in regulation of ER and mitochondrial function. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau. © 2014.

Proteostasis Therapeutics | Date: 2014-07-17

The present invention is directed to compounds having the Formula (I), (Ia) or (Ib), compositions thereof and methods for the treatment of a condition associated with a dysfunction in proteostasis.

Proteostasis Therapeutics | Date: 2014-07-17

The present invention is directed to compounds having the Formula (I), (Ia) or (Ib), compositions thereof and methods for the treatment of a condition associated with a dysfunction in proteostasis.

News Article | November 4, 2014
Site: www.xconomy.com

Proteostasis Therapeutics got a new CEO a few months ago; now the Cambridge, MA-based startup has a new development deal to work on, and a new high-profile investor too. Japanese drugmaker Astellas Pharma inked a partnership today with Proteostasis to try to discover and develop new drugs for an unspecified genetic disease and, potentially, other unnamed disease types. Proteostasis is getting an upfront check of an undisclosed amount . The deal includes a lot of “bio-bucks,” however: downstream payments that could materialize should Proteostasis hit a variety of development milestones. Specifically, Proteostasis could get up to $400 million in payments if it hits a series of targets on a drug the two companies will develop together. Astellas also has the option to start up two additional programs with Proteostasis on the same terms. So in theory, if all three development projects hit all of their goals, Proteostasis stands to get as much as $1.2 billion. It also has an option to split the rights, both domestically and internationally, to the drug candidates in the partnership. Astellas has also made an unspecified equity investment in Proteostasis as part of the deal. The two companies will try to harness Proteostasis’s work in the field of protein homeostasis, or the ability of cells to properly manufacture or deactivate proteins. When this process is upset, like through genetic disorders or aging, proteins do things they aren’t supposed to do, which can lead to diseases. Proteostasis is one of a handful of companies, including Forma Therapeutics, trying to use drugs that can reestablish homeostasis after it’s been perturbed. Proteostasis is still far away from proving itself. The company’s lead drug candidate, for cystic fibrosis, is in preclinical development. But the company has made a few strategic moves over the past year. First, in December, it added Biogen Idec (NASDAQ: BIIB) as an investor as part of a deal to develop drugs for neurodegenerative diseases. Then, in June, it named Meenu Chhabra, the former head of Seattle-based Allozyne (which is now defunct), its new president and CEO. Proteostasis’s previous CEO was Mark Enyedy, who left the company to become the head of Shire’s internal medicine unit in August 2013—he’s now Shire’s head of corporate development. With Astellas on board, Proteostasis now has three pharmaceutical companies in its investor syndicate—the others being Sanofi (via Sanofi-Genzyme BioVentures) and Novartis. Elan, which is now owned by Perrigo, is also an investor. As for the Astellas deal, the two companies aim to make drugs that modulate what’s known as the “unfolded protein response,” a cellular stress reaction that occurs when proteins in the endoplasmic reticulum don’t fold properly. Proteostasis says this happens in a number of genetic, neurodegenerative, and other diseases. The first program will zero in on an unspecified genetic disease. Proteostasis started up in 2008 with a big $45 million round from HealthCare Ventures, Fidelity Biosciences, New Enterprise Associates, Novartis Option Fund, and Genzyme.

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