Click Chemistry to Probe Hsp90: Synthesis and Evaluation of a Series of Triazole Containing Novobiocin Analogues

A series of triazole-containing novobiocin analogues has been designed, synthesized and their inhibitory activity determined. These compounds contain a triazole ring in lieu of the amide moiety present in the natural product. The anti-proliferative effects of these compounds were evaluated against two breast cancer cell lines (SKBr-3 and MCF-7), and manifested activities similar to their amide-containing counterparts. In addition, Hsp90-dependent client protein degradation was observed via western blot analysis, further supporting a common mode of Hsp90 inhibition for both structural classes

The Comparability of Men Who Have Sex With Men Recruited From Venue-Time-Space Sampling and Facebook: A Cohort Study

Background: Recruiting valid samples of men who have sex with men (MSM) is a key component of the US human immunodeficiency virus (HIV) surveillance and of research studies seeking to improve HIV prevention for MSM. Social media, such as Facebook, may present an opportunity to reach broad samples of MSM, but the extent to which those samples are comparable with men recruited from venue-based, time-space sampling (VBTS) is unknown. Objective: The objective of this study was to assess the comparability of MSM recruited via VBTS and Facebook. Methods: HIV-negative and HIV-positive black and white MSM were recruited from June 2010 to December 2012 using VBTS and Facebook in Atlanta, GA. We compared the self-reported venue attendance, demographic characteristics, sexual and risk behaviors, history of HIV-testing, and HIV and sexually transmitted infection (STI) prevalence between Facebook- and VTBS-recruited MSM overall and by race. Multivariate logistic and negative binomial models estimated age/race adjusted ratios. The Kaplan-Meier method was used to assess 24-month retention. Results: We recruited 803 MSM, of whom 110 (34/110, 30.9% black MSM, 76/110, 69.1% white MSM) were recruited via Facebook and 693 (420/693, 60.6% black MSM, 273/693, 39.4% white MSM) were recruited through VTBS. Facebook recruits had high rates of venue attendance in the previous month (26/34, 77% among black and 71/76, 93% among white MSM; between-race P=.01). MSM recruited on Facebook were generally older, with significant age differences among black MSM (P=.02), but not white MSM (P=.14). … See full text for complete abstract

The Black Hole Mass of NGC 4151. II. Stellar Dynamical Measurement from Near-Infrared Integral Field Spectroscopy

We present a revised measurement of the mass of the central black hole (Mbh) in the Seyfert 1 galaxy NGC 4151. The new stellar dynamical mass measurement is derived by applying an axisymmetric orbit-superposition code to near-infrared integral field data obtained using adaptive optics with the Gemini NIFS spectrograph. When our models attempt to fit both the NIFS kinematics and additional low spatial resolution kinematics, our results depend sensitively on how chi-squared is computed--probably a consequence of complex bar kinematics that manifest immediately outside the nuclear region. The most robust results are obtained when only the high spatial resolution kinematic constraints in the nuclear region are included in the fit. Our best estimates for the BH mass and H-band mass-to-light ratio are Mbh~(3.76+/-1.15)E7 Msun (1-sigma error) and M/L(H-band)~0.34+/-0.03 Msun/Lsun (3-sigma error), respectively (the quoted errors reflect the model uncertainties). Our BH mass measurement is consistent with estimates from both reverberation mapping (3.57[+0.45/-0.37]E7 Msun) and gas kinematics (3.0[+0.75/-2.2]E7 Msun; 1-sigma errors), and our best-fit mass-to-light ratio is consistent with the photometric estimate of M/L(H-band)=0.4+/-0.2 Msun/Lsun. The NIFS kinematics give a central bulge velocity dispersion sigma_c=116+/-3 km/s, bringing this object slightly closer to the M-sigma relation for quiescent galaxies. Although NGC 4151 is one of only a few Seyfert 1 galaxies in which it is possible to obtain a direct dynamical BH mass measurement--and thus, an independent calibration of the reverberation mapping mass scale--the complex bar kinematics makes it less than ideally suited for this purpose.Comment: 21 pages, 15 figures. Accepted for publication in Ap

Gambogic Acid, a Natural Product Inhibitor of Hsp90

A high-throughput screening of natural product libraries identified (−)-gambogic acid (1), a component of the exudate of Garcinia harburyi, as a potential Hsp90 inhibitor, in addition to the known Hsp90 inhibitor celastrol (2). Subsequent testing established that 1 inhibited cell proliferation, brought about the degradation of Hsp90 client proteins in cultured cells, and induced the expression of Hsp70 and Hsp90, which are hallmarks of Hsp90 inhibition. Gambogic acid also disrupted the interaction of Hsp90, Hsp70, and Cdc37 with the heme-regulated eIF2α kinase (HRI, an Hsp90-dependent client) and blocked the maturation of HRI in vitro. Surface plasmon resonance spectroscopy indicated that 1 bound to the N-terminal domain of Hsp90 with a low micromolar Kd, in a manner that was not competitive with the Hsp90 inhibitor geldanamycin (3). Molecular docking experiments supported the posit that 1 binds Hsp90 at a site distinct from Hsp90s ATP binding pocket. The data obtained have firmly established 1 as a novel Hsp90 inhibitor and have provided evidence of a new site that can be targeted for the development of improved Hsp90 inhibitors

Synthesis and Evaluation of Novologues as C-Terminal Hsp90 Inhibitors with Cytoprotective Activity against Sensory Neuron Glucotoxicity

Compound 2 (KU-32) is a first-generation novologue (a novobiocin-based, C-terminal, heat shock protein 90 (Hsp90) inhibitor), that decreases glucose-induced death of primary sensory neurons and reverses numerous clinical indices of diabetic peripheral neuropathy in mice. The current study sought to exploit the C-terminal binding site of Hsp90 to determine whether the optimization of hydrogen bonding and hydrophobic interactions of second generation novologues could enhance neuroprotective activity. Using a series of substituted phenylboronic acids to replace the coumarin lactone of 2, we identified electronegative atoms placed at the meta-position of the B-ring exhibit improved cytoprotective activity, which is believed to result from favorable interactions with Lys539 in the Hsp90 C-terminal binding pocket. Consistent with these results, a meta-3-fluorophenyl substituted novologue (13b) exhibited a 14-fold lower ED50 compared to 2 for protection against glucose-induced toxicity of primary sensory neurons

Targeting the Heat Shock Protein 90 Dimer with Dimeric Inhibitors

The design, synthesis and biological evaluation of conformationally constrained coumermycin A1 analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3mm2, A549 and HT29) cell lines. Non-noviosylated coumermycin A1 analogues that manifest potent anti-proliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in ~100 fold increase in anti-proliferative activities as compared to coumermycin A1, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities

Using the Persuasive Design Model to Refine a Novel Stimuli Responsive Polymeric Sensor in Head and Neck Cancer Patients

https://openworks.mdanderson.org/sumexp22/1143/thumbnail.jp

Family history of cancer and head and neck cancer survival

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137774/1/lary26524_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137774/2/lary26524.pd

Stability of methylation markers in head and neck squamous cell carcinoma

BackgroundAs cancer progresses, methylation patterns change to promote the tumorigenic phenotype. However, stability of methylation markers over time and the extent that biopsy samples are representative of larger tumor specimens are unknown. This information is critical for clinical use of such biomarkers.MethodsNinety‐eight patients with tumor specimens from 2 timepoints were measured for DNA methylation in the promoter regions across 4 genes.ResultsThere were no significant differences in overall methylation of CCNA1 (cyclin A1), NDN (necdin), deleted in colorectal carcinoma (DCC), and cluster of differentiation 1a (CD1A) within paired specimens (p values = .56, .17, .66, and .58, respectively). All genes showed strong correlations between paired specimens across time. Methylation was most consistent for CCNA1 and NDN over time.ConclusionThis report provides the first evidence that methylation markers measured in biopsy samples are representative of gene methylation in later specimens and suggests that biopsy markers could be representative biomarkers for use in defining personalized treatment utilizing epigenetic changes. © 2015 Wiley Periodicals, Head Neck 38: E1325–E1331, 2016Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137576/1/hed24223.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137576/2/hed24223_am.pd

Development of a Grp94 inhibitor

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ja303477g.Heat shock protein 90 (Hsp90) represents a promising therapeutic target for the treatment of cancer and other diseases. Unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms. Using a structure-based approach, we designed an inhibitor of Grp94, the ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 and Hsp90α/β (cytosolic isoforms) clients were investigated. Compound 2 prevented intracellular trafficking of the Toll receptor, inhibited the secretion of IGF-II, affected the conformation of Grp94, and suppressed Drosophila larval growth, all Grp94-dependent processes. In contrast, compound 2 had no effect on cell viability or cytosolic Hsp90α/β client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein