GRP78 inhibitor YUM70 upregulates 4E-BP1 and suppresses c-MYC expression and viability of oncogenic c-MYC tumors.

The 78-kDa glucose regulated protein (GRP78) commonly upregulated in a wide variety of tumors is an important prognostic marker and a promising target for suppressing tumorigenesis and treatment resistance. While GRP78 is well established as a major endoplasmic reticulum (ER) chaperone with anti-apoptotic properties and a master regulator of the unfolded protein response, its new role as a regulator of oncoprotein expression is just emerging. MYC is dysregulated in about 70 % of human cancers and is the most commonly activated oncoprotein.

Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations.

KRAS is the most commonly mutated oncogene in human cancers with limited therapeutic options, thus there is a critical need to identify novel targets and inhibiting agents. The 78-kDa glucose-regulated protein GRP78, which is upregulated in KRAS cancers, is an essential chaperone and the master regulator of the unfolded protein response (UPR). Following up on our recent discoveries that GRP78 haploinsufficiency suppresses both KRAS-driven pancreatic and lung tumorigenesis, we seek to determine the underlying mechanisms.

The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress-Mediated Apoptosis in Pancreatic Cancer.

GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death.

Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma.

Epithelial ovarian cancer (EOC) is a leading cause of cancer-related mortality in the United States due to the late-stage disease at diagnosis. Overexpression of GRP78 and PDI following endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) promote growth and invasion in cancer. To identify novel prognostic biomarkers in EOC, here we determined the expression of ER stress-associated proteins (GRP78, ATF6 and PERK) and correlated with clinical outcome in EOC.

Structure-Based Design of N-(5-Phenylthiazol-2-yl)acrylamides as Novel and Potent Glutathione S-Transferase Omega 1 Inhibitors.

Using reported glutathione S-transferase omega 1 (GSTO1-1) cocrystal structures, we designed and synthesized acrylamide-containing compounds that covalently bind to Cys32 on the catalytic site. Starting from a thiazole derivative 10 (GSTO1-1 IC = 0.6 μM), compound 18 was synthesized and cocrystallized with GSTO1.

Expression of protein disulfide isomerase family members correlates with tumor progression and patient survival in ovarian cancer.

Objective: Protein disulfide isomerase (PDI) is an oxidoreductase that is overexpressed in several cancers. PDI family members (PDIs) play a role in various diseases including cancer. Select PDIs were reported as useful markers in other cancers but their expression in ovarian cancer has not been thoroughly assessed.

Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma.

Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium-throughput 20 000-compound screen of a diverse subset of 1 000 000 compounds to identify cytotoxic small molecules.

Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor.

Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we show that silencing of GSTO1 with siRNA significantly impairs cancer cell viability, validating GSTO1 as a potential new target in oncology.

Sequence and membrane determinants of the random coil-helix transition of α-synuclein.

A random coil-helix transition underlies the association of the presynaptic protein α-synuclein (αS) with curved vesicle membranes to fold Asp2-Ala89 into a continuous helix. To clarify this transition, we examined αS folding cooperativity, helix nucleation and propagation in relation to membrane stabilization and leakage on diverse small unilamellar vesicles. The sequences centering on Phe4 and Tyr39 initiate lipid interactions and the Phe4 region nucleates the helix irrespective of the order of Ser9-Ala89.

Structural characterization of the regulatory domain of brain carnitine palmitoyltransferase 1.

Neurons contain a mammalian-specific isoform of the enzyme carnitine palmitoyltransferase 1 (CPT1C) that couples malonyl-CoA to ceramide levels thereby contributing to systemic energy homeostasis and feeding behavior. In contrast to CPT1A, which controls the rate-limiting step of long-chain fatty acid β-oxidation in all tissues, the biochemical context and regulatory mechanism of CPT1C are unknown. CPT1 enzymes are comprised of an N-terminal regulatory domain and a C-terminal catalytic domain (CD) that are separated by two transmembrane helices.

Possible anticancer agents: QSAR analogs of glutamamide: synthesis and pharmacological activity of 1,5-N,N'-disubstituted-2-(substituted benzenesulphonyl) glutamamides.

Based on our earlier QSAR prediction, a series of designed QSAR analogs of 1,5-N,N'-disubstituted-2-(substituted benzenesulphonyl) glutamamides were synthesized as possible anticancer agents. Inhibitions of tumor cell proliferation of the compounds were tested in tumor cell line IMR-32. Anticancer activities of these compounds were also evaluated on Swiss Albino mice against Ehrlich Ascites Carcinoma (EAC) cells.

QSAR modelling of pancreatic beta-cell KATP channel openers R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans using MLR-FA techniques.

Potassium (K(+)) channel openers are a diverse group of compounds which are used for the treatment of diseases like angina pectoris, hypertension, congestive heart failure, anti-hypoglycemic (insulinoma), bronchial asthma, etc. R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-cells. QSAR modelling was done on these series of compounds to find a more active and selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues.

Chemoimmunotherapeutic approach to prolonged survival time in combination with immunization and glutamic Acid derivatives with antitumor activity in tumor-bearing mice.

Cancer is one of the major causes of death. For cancer, the general conventional treatment and standard of care for clinical oncology remains surgery followed by radiation and/or systemic chemotherapy as deemed appropriate based on the clinical findings. Chemoimmunotherapy is an approach to treat cancer where chemotherapy is given along with immunotherapy.

Antibacterial activity of Abies webbiana.

The methanol extract of the dried leaves of Abies webbiana was evaluated for antimicrobial activity. The methanol extract showed a broad spectrum of antibacterial activity.

Exploring QSAR on 3-aminopyrazoles as antitumor agents for their inhibitory activity of CDK2/cyclin A.

Chemical inhibitors of cyclin-dependent kinases have great therapeutic potential against various proliferative and neurodegenerative disorders. The pharmacophoric requirement of 3-aminopyrazole, inhibitors of CDK2/cyclin A as antitumor agents was explored. QSAR study was performed using ETSA index, RTSA index, indicator parameters and atomic charges to consider quantitatively the effect of the structural variation on the antitumor activity of 3-aminopyrazole.

QSAR modeling on dopamine D2 receptor binding affinity of 6-methoxy benzamides.

QSAR modeling was performed on 58 (S) N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxy benzamides as dopamine (DA) D2 receptor antagonists to identify the structural requirements for DA D2 receptor binding affinity. The study pointed out that the presence of hydrophobic substituents at R3 position and electron-donating groups at R5 position increased the biological activity. Substitutions at phenyl ring favored the binding affinity of these benzamides.

QSAR study on some anti-HIV HEPT analogues using physicochemical and topological parameters.

A Quantitative Structure-Activity Relationship (QSAR) study has been carried out using topological indices, physicochemical and indicator parameters on a series of HEPT analogues for their HIV reverse transcriptase inhibitory activity. Correlation analysis and multiple linear regression (MLR) method were used to find out the best QSAR model. The results clearly explained that decreased hydrophobicity of substituents at R(1) and R(2) positions are favorable for the activity and presence of di-substitution at phenyl ring as well as i-Pr at R(1) position have detrimental effect but presence of OH group at R(2) position increases the activity.

5-N-Substituted-2-(substituted benzenesulphonyl) glutamines as antitumor agents. Part II: synthesis, biological activity and QSAR study.

Cancer is a major killer disease throughout human history. Thus, cancer becomes a major point of interest in life science. It was proved that cancer is a nitrogen trap and tumor cells are avid glutamine consumers.

QSAR study on some pyridoacridine ascididemin analogues as anti-tumor agents.

Pyridoacridine ascididemin analogues have been reported as anticancer agents for their interesting antitumor activity against human cancer cells. A quantitative structure-activity relationship (QSAR) analysis of ascididemin analogues was attempted using the physicochemical parameters and the electrotopological state atom (ETSA) indices. This study indicates that the electron withdrawing substituents with higher MR (molar refractivity) value at R(1) position favor the anti-tumor activity and the presence of NHR (R is hydrogen or alkyl group) at the R(3) position has contribution to the anti-tumor activity.

QSAR study on the affinity of some arylpiperazines towards the 5-HT1A/alpha1-adrenergic receptor using the E-state index.

QSAR models represent the relationship of biological activity with either physicochemical parameters or structural indices. QSAR study was performed on some arylpiperazines as 5-HT(1A)/alpha(1)-adrenergic receptor antagonists using E-state indices to identify the pharmacophoric requirements. It was found that some of the atoms played important roles to both activities and some played important role in selectivity of compound to the 5-HT(1A) antagonistic activity.

QSAR study on some p-arylthio cinnamides as antagonists of biochemical ICAM-1/LFA-1 interaction and ICAM-1/JY-8 cell adhesion in relation to anti-inflammatory activity.

In an attempt to find out the chemical and structural features of some p-arylthio cinnamides 1 as antagonists of biochemical ICAM-1/LFA-1 interaction as well as ICAM-1/JY-8 cell adhesion in relation to anti-inflammatory activity, QSAR study was performed. Steric effect on the arylthio ring and lipophilic substitutions at 2,3-positions, especially 2,3-disubstitution with Cl or CF(3) or both on cinnamides 1 were conducive to the activity, whereas simultaneous presence of methoxy group at arylthio ring and NCOCH(3) group at heterocyclic ring of cinnamides 1 were detrimental to activity in antagonism of biochemical ICAM-1/LFA-1 interaction. When inhibition of ICAM-1/JY-8 cell adhesion was considered, lipophilic substitution on ring B and simultaneous presence of CF(3) groups at 2 and 3 positions of the ring B were advantageous to antagonism.