Durham, NC, United States
Durham, NC, United States

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Putcha P.,Massachusetts General Hospital | Danzer K.M.,Massachusetts General Hospital | Kranich L.R.,Massachusetts General Hospital | Scott A.,Serenex Inc. | And 7 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Aggregation of α-synuclein (αsyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and dementia with Lewy bodies. Lewy bodies contain αsyn and several heat shock proteins (Hsp), a family of molecular chaperones up-regulated by the cell under stress. We have previously shown that direct expression of Hsp70 and pharmacological up-regulation of Hsp70 by geldanamycin, an Hsp90 inhibitor, are protective against αsyninduced toxicity and prevent aggregation in culture. Here, we use a novel protein complementation assay to screen a series of small-molecule Hsp90 inhibitors for their ability to prevent αsyn oligomerization and rescue toxicity. By use of this assay, we found that several compounds prevented αsyn oligomerization as measured by decreased luciferase activity, led to a reduction in high-molecular-mass oligomeric αsyn, and protected against αsyn cytotoxicity. A lead compound, SNX-0723 (2-fluoro-6-[(3S)-tetrahydrofuran-3- ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide) was determined to have an EC50 for inhibition of αsyn oligomerization of approximately 48 nM and was able to rescue αsyn-induced toxicity. In vivo assessment of SNX-0723 showed significant brain concentrations along with induction of brain Hsp70. With a low EC50, brain permeability, and oral availability, these novel inhibitors represent an exciting new therapeutic strategy for PD. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.


Fadden P.,Serenex Inc. | Huang K.H.,Serenex Inc. | Veal J.M.,Serenex Inc. | Steed P.M.,Serenex Inc. | And 25 more authors.
Chemistry and Biology | Year: 2010

A chemoproteomics-based drug discovery strategy is presented that utilizes a highly parallel screening platform, encompassing more than 1000 targets, with a focused chemical library prior to target selection. This chemoproteomics-based process enables a data-driven selection of both the biological target and chemical hit after the screen is complete. The methodology has been exemplified for the purine binding proteome (proteins utilizing ATP, NAD, FAD). Screening of an 8000 member library yielded over 1500 unique protein-ligand interactions, which included novel hits for the oncology target Hsp90. The approach, which also provides broad target selectivity information, was used to drive the identification of a potent and orally active Hsp90 inhibitor, SNX-5422, which is currently in phase 1 clinical studies. © 2010 Elsevier Ltd.


Duan S.,AMRI | Venkatraman S.,AMRI | Hong X.,AMRI | Huang K.,Serenex Inc. | And 7 more authors.
Organic Process Research and Development | Year: 2012

A scalable process for the manufacture of a Hsp90 inhibitor was developed and optimized. Key features in the seven-step process include a selective S NAr reaction followed by an Ullmann-type coupling of indazolone to an aryl halide. This improved process afforded 65% yield over two critical steps compared to 25% following the Medicinal Chemistry route. © 2012 American Chemical Society.


Patent
Serenex Inc. | Date: 2010-10-19

Disclosed are compounds and pharmaceutically acceptable salts of Formula I wherein R_(1), R_(2), R_(3), R_(4), R_(5), R_(6), R_(7), n, Q_(1), Q_(2), Q_(3), Y, and X_(1)-X_(4 )are as defined herein. Compounds of Formula I are useful in the treatment of diseases and/or conditions related to cell proliferation, such as cancer, inflammation, arthritis, angiogenesis, or the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.


Patent
Serenex Inc. | Date: 2011-10-26

Disclosed are compounds and pharmaceutically acceptable salts of Formula (I) : wherein R_(1), R_(2), R_(3), R_(4), R_(5), R_(6), R_(7), n, Q1, Q2, Q3, Y, and X_(1)-X_(4) are as defined herein. Compounds of Formula (I) are useful in the treatment of diseases and/or conditions related to cell proliferation, such as cancer, inflammation, arthritis, angiogenesis, or the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.


Inhibition of Hsp90 has emerged as a therapeutic strategy to target NSCLC subtypes, which are refractory to epidermal growth factor receptor (EGFR) inhibitor-based treatment. We report on a novel small molecule inhibitor of Hsp90, SNX-2112, and an orally bioavailable prodrug analog, SNX-5422. In cellular models of wild-type or mutant EGFR (L858R and T790M mutations), SNX-2112 alone and in combination with erlotinib inhibited EGF activation of pAKT(473) and pSTAT3(705). pERK1/2 and pS6 were also potently inhibited by similar treatments. SNX-2112 reduced EGF cross-talk and activation of the c-Met receptor by causing c-Met degradation. In NCI-H1975 xenograft models, SNX-5422 showed activity as a single agent and in combination with erlotinib resulted in prolonged animal survival at reduced compound concentrations relative to either compound alone. These results support the advanced evaluation of SNX-5422 as a treatment for non-small cell lung cancer (NSCLC), especially in cases where the cancer is driven by c-Met amplification or mutated EGFR forms that are resistant to EGFR inhibitors.


Patent
Serenex Inc. | Date: 2011-04-07

Disclosed are compounds and pharmaceutically acceptable salts of Formula I wherein R_(1), R_(2), R_(3), R_(4), R_(5), R_(6), R_(7), n, Q_(1), Q_(2), Q_(3), Y, and X_(1)-X_(4 )are as defined herein. Compounds of Formula I are useful in the treatment of diseases and/or conditions related to cell proliferation, such as cancer, inflammation, arthritis, angiogenesis, or the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.


PubMed | Serenex Inc.
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2012

A novel class of Hsp90 inhibitors, structurally distinct from previously reported scaffolds, was developed from rational design and optimization of a compound library screen hit. These aminoquinazoline derivatives, represented by compound 15 (SNX-6833) or 1-(2-amino-4-methylquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one, selectively bind to Hsp90 and inhibit its cellular activities at concentrations as low as single digit nanomolar.


PubMed | Serenex Inc
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

14613 Background: SNX-5422 is an oral pro-drug of SNX-2112, a potent and highly selective small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). SNX-2112 potently inhibits solid and hematological tumor cell proliferation with IC50 values of 1-10 nM, and is more potent than 17-AAG and 17-DMAG in a majority of the cell lines tested. Due to its involvement in the maturation and maintenance of numerous proteins critical for tumor cell viability and growth, Hsp90 is an exciting therapeutic target for a broad range of solid tumor and hematological malignancies.Eligibility included patients (pt) with refractory solid tumors or lymphomas, Karnofsky performance status 60, adequate organ function, and no known CNS involvement, primary or metastatic. SNX-5422 was given orally every other day daily for 21 days followed by 7 days of rest. Dose escalation is proceeding at 100% with standard 3 pt cohorts until a grade (gr) 2 adverse event (AE) occurs, then escalation decreases to 33%. The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, and PK of SNX-5422.11 patients have been dosed to date; 3 in cohort 1 (4 mg/mSNX-5422 has been well tolerated through the first three dose levels and is enrolling at 21.28 mg/m


PubMed | Serenex Inc
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

13067 Background: The preclinical and clinical data evaluating derivatives of the natural product geldanamycin, including 17-AAG and 17-DMAG, reveal that inhibition of the molecular chaperone HSP90 results in multiple anti-tumor effects. SNX-5422 and SNX-5542 are potent, novel, highly specific, water soluble and orally active small molecule inhibitors of Hsp90. Here we describe the preclinical efficacy and toxicity evaluation of these compounds.The PK profile of SNX-5422 and SNX-5542 was determined following oral and iv dosing in mice and rats. HT29 xenografts were performed oral doses of SNX-5542 on a schedule of Q2DX3,2 for 2 weeks or 17-DMAG on the previously reported regimen of bid5,2 for 2 weeks, with tumor progression and body weight monitored. Plasma, tumor and other tissues were harvested for evaluation of HSP70 induction and levels of HSP90 client proteins. Rats were treated with varying oral doses on a schedule of Q2DX3,2 for two weeks. Clinical observations were noted and standard hematology and clinical chemistry parameters were monitored.SNX-5542 exhibited 37% oral BA in rats and >75% in mice, with tSNX small-molecule HSP90 inhibitors have favorable pharmacokinetic profiles, oral bioavailability, tolerability and superior anti-tumor activity compared to the natural product derivative 17-DMAG. [Table: see text].

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