Reduced Side Effect Profile Research Articles

Mirogabalin: a novel gabapentinoid or another false dawn?

Mirogabalin is a novel gabapentinoid medication for the treatment of neuropathic pain. The purpose of this review is to discuss current evidence for its use. Gabapentinoids are widely prescribed for neuropathic pain. Mirogabalin offers theoretical advantages over traditional gabapentinoids due to its specificity for the α2δ-1 subunit of voltage-gated calcium channels. It is theorised that this specificity may reduce adverse drug reactions by minimising binding to the α2δ-2 subunit which is responsible for many of the gabapentinoid side effects. Mirogabalin's slower dissociation from the α2δ-1 compared with α2δ-2, and its higher potency may also impart an efficacy benefit over traditional gabapentinoids. These theoretical advantages of mirogabalin remain inconclusive in clinical practice, with mixed evidence regarding mirogabalin versus traditional gabapentinoids. Some studies suggest a reduced side effect profile yet, others fail to demonstrate significant differences. Regarding efficacy, mirogabalin may be superior to placebo for several neuropathic pain syndromes, but evidence of widespread benefit over traditional gabapentinoids is currently lacking. Mirogabalin offers theoretical promise, but large, independent studies are required to further assess its performance versus traditional gabapentinoids.

Selective Modulation of the Human Glucocorticoid Receptor Compromises GR Chromatin Occupancy and Recruitment of p300/CBP and the Mediator Complex

Exogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts for the treatment of solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic. GR is a member of the nuclear receptor family of transcription factors and heavily relies on interactions with coregulator proteins for its transcriptional activity. To elucidate the role of the GR interactome in the differential transcriptional activity of GR following treatment with the selective GR agonist and modulator dagrocorat compared to classic (ant)agonists, we generated comprehensive interactome maps by high-confidence proximity proteomics in lung epithelial carcinoma cells. We found that dagrocorat and the antagonist RU486 both reduced GR interaction with CREB-binding protein/p300 and the mediator complex compared to the full GR agonist dexamethasone. Chromatin immunoprecipitation assays revealed that these changes in GR interactome were accompanied by reduced GR chromatin occupancy with dagrocorat and RU486. Our data offer new insights into the role of differential coregulator recruitment in shaping ligand-specific GR-mediated transcriptional responses.

Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Cavα2δ-1 Subunit of Voltage-Gated Calcium Channel and the μ-Opioid Receptor.

The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the μ-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Cavα2δ-1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino-acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug-drug interactions. A representative compound, (2S,4S)-4-(4-chloro-3-(((cis)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid, displayed promising analgesic activities in several in vivo pain models as well as a reduced side-effect profile in relation to morphine.

Patient Preferences for Adjuvant Treatment in Muscle-Invasive Urothelial Carcinoma: A Multi-Country Discrete Choice Experiment.

The evolving treatment landscape in muscle-invasive urothelial carcinoma creates challenges for clinicians and patients in selecting the most appropriate therapy. Here, we aimed to understand adjuvant treatment preferences among patients with muscle-invasive urothelial carcinoma who underwent radical resection, including tradeoffs between efficacy outcomes and toxicity risks. An observational, cross-sectional study utilizing a discrete choice experiment was conducted across the United States, United Kingdom, Canada, France, and Germany via a web-based survey. Patients ≥18years of age who self-reported as having been diagnosed with muscle-invasive urothelial carcinoma were included. Patients indicated their preferences between hypothetical treatment profiles varying in eight attributes relating to efficacy, regimen, and side effects. Preference weights were estimated using hierarchical Bayesian logistic regression; relative attribute importance estimates were calculated. Overall, 207 patients were included (age ≥56 years, 65.7%; male, 54.1%). Patients chose adjuvant treatment 91.2% of the time vs no treatment. Prolonging overall survival from 25 to 78 months was most important, followed by reducing serious side effect risks. Increasing disease-free survival from 12 to 24 months was more important than decreasing risks of fatigue from 54% to 15% and nausea from 53% to 7%. Treatment with the shortest dosing regimen was more important for patients who received neoadjuvant chemotherapy vs patients who did not receive neoadjuvant chemotherapy; prolonging overall survival was more important than reducing the risk of a serious side effect in non-US patients; the opposite was found in the United States. Patients with muscle-invasive urothelial carcinoma who underwent radical resection preferred adjuvant treatment over no treatment regardless of side effects. Patients prioritized overall survival improvements followed by a reduced side effect profile.

A prospective study on the efficacy and safety of fractional carbon dioxide laser in the treatment of post-acne scars

Introduction Acne scars can play havoc with the social functioning of the patient leading to severe depression with reduced quality of life. Fractional CO2 laser provides a fine balance between the undesirable side effects of ablative lasers and the limited efficacy of nonablative lasers. Objective The present study was conducted to evaluate the efficacy and safety of fractional CO2 laser in the treatment of acne scars. Patients and methods Fractional CO2 laser treatment performed on 30 patients with atrophic acne scar by different protocols depending on the type and its depth. Results were assessed based on serial photographs, clinical improvement, and physician’s global assessment scale. Results Of the 30 participants, 27 completed all three sessions. Out of the 27 patients in the final follow-up, three (10%) had excellent improvement of which two had mild acne scar and one had moderate scar before treatment; 16 (59.2%) had good response of which 13 had moderate acne scar and three had mild scar and eight (29.7%) had fair response of which six had moderate scars and two had mild scars. Conclusion Fractional CO2 laser as monotherapy in the treatment of mild-to-moderate post-acne scars seems to be effective with good patient satisfaction and reduced side effect profile. In case of severe acne scars, fractional CO2 laser can be used as a combined procedure along with other therapeutic modalities like subcision, platelet-rich plasma, and TCA CROSS (chemical reconstruction of skin scars using trichloroacetic acid) techniques.

Discovery of novel non-steroidal selective glucocorticoid receptor modulators by structure- and IGN-based virtual screening, structural optimization, and biological evaluation

Glucocorticoids (GCs) are the most commonly used anti-inflammatory drugs. However, their excellent therapeutic effects are often accompanied by undesirable side effects. To discover selective glucocorticoid receptor modulators (SGRMs) that preferentially induce transrepression with little or no transactivation activity, a structure-based virtual screening by combining molecular docking and InteractionGraphNet (IGN) rescoring was performed, and compound HP210 was identified. HP210 did not induce the transactivation functions of GR while still acted on the NF-κB mediated tethered transrepression function (IC50 = 2.32 μM), and suppressed the secretion of pro-inflammation cytokines IL-1β and IL-6. Compared with dexamethasone, HP210 showed no cross activities with phylogenetically related mineralcorticoid receptor and progesterone receptor and no significant effect on osteoprotegerin, exhibiting a reduced side-effect profile. Then, guided by the molecular dynamics simulations and binding free energy calculations, compound HP210_b4 with over two-fold higher transrepression activity (IC50 = 0.99 μM) was discovered. This study reported a group of non-steroidal new-scaffold SGRMs, providing valuable clues for the development of novel anti-inflammatory drugs.

Anti-inflammatory action of betulin and its potential as a dissociated glucocorticoid receptor modulator

Although the medical application of betulin has been presented in previous studies, the potential mechanism of the anti-inflammatory action of betulin should be further investigated. This work aims to confirm the hypothesis that betulin has dexamethasone-like anti-inflammatory action through glucocorticoid receptor (GR)-mediated pathway. Firstly, the binding ability of betulin with GR was measured by a fluorescence polarization-based competitive binding assay, with the IC50 value of 79.18 ± 0.30 mM. Betulin could bind to GR and then induced GR nuclear translocation, but lacked GR transcriptional activity in HeLa cells. Hence, betulin exhibited the potential to be a dissociated modulator for GR, with the loss of glucocorticoid response element (GRE)-associated side effects. In addition, betulin downregulated GRE-driven protein expression of G6P involved in gluconeogenesis, namely side effect. The results of pro-inflammatory cytokines analysis showed that betulin exerted anti-inflammatory action in vitro. Both of the hydrophobic and hydrogen-bonding interactions stabilized the binding between betulin and GR during the simulation process. In conclusion, betulin might be a potential dissociated GR modulator with a reduced side effect profile yet keeping its anti-inflammatory action.

Momelotinib and Citarinostat: Co-Targeting JAK2/STAT3 and HDAC6 in Lymphoid Malignancies, a New Potential Therapeutic Combination

Background . The JAK2/STAT3 signaling pathway is abnormally activated in hematological malignancies. HDAC6 has been reported to be overexpressed in primary and cultured multiple myeloma cells and B and T-cell lymphoma. Momelotinib (CYT-387) is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. Citarinostat (ACY-241), a second generation HDAC6 selective inhibitor, has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor drugs candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness. Both drugs are currently under investigation in clinical trials, they show a good toxicity profile and are both orally available.Methods. Screening: momelotinib and citarinostat alone and in combination were tested in 12 lymphoid malignant cell lines: B-cell lymphomas (WSU-NHL, RL, Karpas-422), mantle cell lymphoma (Granta-519, Jeko-1), cutaneous T cell lymphoma (Hut-78), anaplastic large cell lymphoma (Karpas-299), Hodgkin lymphoma (L-1236, L-540), multiple myeloma (U266, RPMI8266) and chronic lymphocytic leukemia (MEC-1). IC50 values of each drug were calculated based on momelotinib concentrations (1 - 10 μM), and citarinostat (1- 100 μM) after 24 - 48 h. Serial dilutions of the two agents were assessed using low concentrations and the interaction was evaluated using the Chou-Talalay method. Cell viability was measured by MTT assay. Cell cycle was determined by flow cytometry. Cell apoptosis was detected by Annexin V/PI staining and apoptosis-related proteins (Bcl2, Bcl-xL, Bax, Bim, PARP and caspase 8) were detected by western blotting. Enzymatic activity of caspases 3, -9 was measured using colorimetric assay. JAK2/STAT3 and the related proteins were analysis by western blotting.Results . Momelotinib alone exhibited anti-proliferation potency in the cell lines examined with IC50 values ranging from 1.8 to 9.6 μM. Exposure for 24 - 48 h with citarinostat alone resulted in time- and dose-dependent inhibition of cell growth with IC50 values ranging from 1.51 to 60 μM. After 24 h, low concentrations of the two drugs, momelotinib (1 μM) and citarinostat (4 μM) had a synergistic effect in WSU-NHL, RL, Karpas-422, Jeko-1, Hut-78, Karpas-299, L-540, RPMI8226 and U266 cells with CI (combination index) values < 1 and antagonist effect in L-1236, Granta-519 and Mec-1 cells with CI > 1. From the panel, we selected three lymphoid cell lines (WSU-NHL, RL, L-540) which were particularly sensitive to the drug combination and two cell lines (L-1236, Granta-519) that showed an IC > 1. While in these cell lines the combination treatment had minimal or no cytotoxic effect, WSU-NHL, RL and L-540 cells showed an increase of cells in sub-G0/G1 phase and a reduction in S phase after 24 h. Compared with single agents, the percentage of apoptotic cells ranged from 35% to 42%. Apoptosis induced by the drug combination was exerted mainly via the mitochondrial apoptotic pathway (intrinsic apoptotic pathway) as demonstrated by upregulation of caspase -9 that was especially evident in WSU-NHL and L-540 with a fold induction of 3.2 and 3.3 compared to control. The apoptosis was associated with activation of caspase-3 and PARP which were prevented by the ZVAD-fmk broad caspase inhibitor. No caspase-8 activation (extrinsic apoptotic pathway) was induced within 24 h of combination treatment. The effect was mediated by the increased expression of the pro-apoptotic proteins Bax and Bim and downregulation of key anti-apoptotic regulators, Bcl2 and Bcl-xL. In addition, momelotinib/citarinostat combination inhibited the phosphorylation of JAK2 and its downstream mediators, including STAT3 and STAT5.Conclusions. These preliminary results indicate that momelotinib can be potentially combined with the HDAC6 inhibitor citarinostat in lymphoid malignancies. Due to the good toxicity profile and the oral administration the combination has the potential for a completely orally therapeutic approach. The study is still ongoing and further investigation is required to better define the underlying molecular mechanisms. DisclosuresNo relevant conflicts of interest to declare.

Modern advancements in minimally invasive surgical treatments for benign prostatic obstruction.

A wide variety of minimally invasive surgical techniques are now being offered for treating voiding lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO). These options offer an alternative to both medical therapy and traditional surgical options. Minimally invasive surgical treatments in LUTS/BPO boast both day case and local anaesthetic options, with a potentially reduced side effect profile compared to traditional surgical interventions matching the needs for a range of patients. We provide a narrative review of minimally invasive surgical treatments available for BPO in terms of the technology, efficacy, safety, institutional recommendations, cost and potential future developments.

Do Newer Antidepressant Drugs Really Have Reduced Side Effects? Examining a Random “Real World” Sample of 300+ Receivers of Medications

Newer antidepressant drugs are frequently cited as having reduced side effect profiles to that of their older counterparts. However, recent studies have begun to dispute this claim, citing selective sampling, short clinical trials, and clinical trial environments as influencing reported outcomes. At present, little research on antidepressant side effects draws on RWD (Real-World Data). Despite this, interest in examining RWD samples for antidepressant drug side effects is increasing as of 2020. The reported study asked a random sample of 300+ individuals taking a variety of different antidepressant medications to complete online drug side effect self-report scales with previously high validity. Newer antidepressants belonging to the atypical antidepressant drug class were reported as having only slightly reduced side effects of weight gain compared with older SSRI-class medications. No reduced side effects of increased depression, anxiety, sexual dysfunction (SD), sleepiness, or suicidal ideation (SI) were found for the newer atypical-class medications vs older SSRI-class agents. Medication adherence did not differ significantly between SSRI and atypical classes. No evidence for reduced side effects was found for newer SSRI and atypical antidepressants vs older same-class drugs when comparing six new and old medications drawn from atypical and SSRI classes. However, atypical antidepressants were associated with increased use of adjunct medications to bolster primary treatment.

Boswellic acids and their derivatives as potent regulators of glucocorticoid receptor actions

Glucocorticoid (GCs) hormones exert their actions via their cognate steroid receptors the Glucocorticoid Receptors (GR), by genomic or non-genomic mechanisms of actions. GCs regulate many cellular functions among them growth, metabolism, immune response and apoptosis. Due to their cell type specific induction of apoptosis GCs are used for the treatment of certain type of cancer. In addition, due to their anti-inflammatory actions, GCs are among the most highly prescribed drug to treat chronic inflammatory disorders, albeit to the many adverse side effects arising by their long term and high doses use. Thus, there is a high need for selective glucocorticoid receptor agonist - modulators (SEGRA- SGRMs) as effective as classic GCs, but with a reduced side effect profile. Boswellic acids (BAs) are triterpenes that show structural similarities with GCs and exhibit anti-inflammatory and anti-cancer activities. In this study we examined whether BA alpha and beta and certain BAs derivatives exert their actions, at least in part, through the regulation of GR activities. Applying docking analysis we found that BAs can bind stably into the deacylcortivazol (DAC) accommodation pocket of GR. Moreover we showed that certain boswellic acids derivatives induce glucocorticoid receptor nuclear translocation, no activation of GRE dependent luciferase gene expression, and suppression of the TNF-α induced NF-κB transcriptional activation in GR positive HeLa and HEK293 cells, but not in low GR level COS-7 cells. Furthermore, certain boswellic acids compounds exert antagonistic effect on the DEX-induced GR transcriptional activation and induce cell type specific mitochondrial dependent apoptosis. Our results indicate that certain BAs are potent selective glucocorticoid receptor regulators and could have great potential for therapeutic use.

In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling.

Interest has emerged in biased agonists at the mu opioid receptor (MOR) as a possible means for maintaining potent analgesis with reduced side effect profiles. While approaches measuring in vitro biased agonism are used in the development of these compounds, their therapeutic utility will ultimately be determined by in vivo functional effects. Nonhuman primates (NHPs) are the most translational model for evaluating the behavioral effects of candidate medications, but biased signaling of these drugs at NHP MOR receptors has been unstudied. The goal of the current work was to characterize MOR ligand bias in rhesus macaques, focusing on agonists that have previously been reported to show different patterns of biased agonism in rodents and humans. Downstream signaling pathways that responded to MOR activation were identified using a luciferase reporter array. Concentration-response curves for specific pathways (cAMP, NF-ĸB, MAPK/JNK) were generated using six agonists previously reported to differ in terms of signaling bias at rodent and human MORs. Using DAMGO as a reference ligand, relative cAMP, NF-ĸB and MAPK/JNK signaling by morphine, endomorphin-1, and TRV130 were found to be comparable between species. Further, the bias patterns of across ligands for NF-ĸB and MAPK/JNK were largely similar between species. There was a high degree of concordance between rhesus macaque and human MOR receptor signaling bias for all agonists tested, further demonstrating their utility for future translational behavioral studies.

Peripherally acting opioid analgesics and peripherally-induced analgesia.

The management of pain, particularly chronic pain, is still an area of medical need. In this context, opioids remain a gold standard for the treatment of pain. However, significant side effects, mainly of central origin, limit their clinical use. Here, we review recent progress to improve the therapeutic and safety profiles of opioids for pain management. Characterization of peripheral opioid-mediated pain mechanisms have been a key component of this process. Several studies identified peripheral µ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively) and nociceptin/orphanin FQ (NOP) receptors as significant players of opioid-mediated antinociception, able to achieve clinically significant effects independently of any central action. Following this, particularly from a medicinal chemistry point of view, main efforts have been directed towards the peripheralization of opioid receptor agonists with the objective of optimizing receptor activity and minimizing central exposure and the associated undesired effects. These activities have allowed the characterization of a great variety of compounds and investigational drugs that show low central nervous system (CNS) penetration (and therefore a reduced side effect profile) yet maintaining the desired opioid-related peripheral antinociceptive activity. These include highly hydrophilic/amphiphilic and massive molecules unable to easily cross lipid membranes, substrates of glycoprotein P (a extrusion pump that avoids CNS penetration), nanocarriers that release the analgesic agent at the site of inflammation and pain, and pH-sensitive opioid agonists that selectively activate at those sites (and represent a new pharmacodynamic paradigm). Hopefully, patients with pain will benefit soon from the incorporation of these new entities.

Cost-Utility Analysis of Electroconvulsive Therapy and Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression in Ontario.

To evaluate the cost-effectiveness of repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT), and combining both treatments in a stepped care pathway for patients with treatment-resistant depression (TRD) in Ontario. A cost-utility analysis evaluated the lifetime costs and benefits to society of rTMS and ECT as first-line treatments for TRD using a Markov model, which simulates the costs and health benefits of patients over their lifetime. Health states included acute treatment, maintenance treatment, remission, and severe depression. Treatment efficacy and health utility data were extracted and synthesized from randomized controlled trials and meta-analyses evaluating these techniques. Direct costing data were obtained from national and provincial costing databases. Indirect costs were derived from government records. Scenario, threshold, and probabilistic sensitivity analyses were performed to test robustness of the results. rTMS dominated ECT, as it was less costly and produced better health outcomes, measured in quality-adjusted life years (QALYs), in the base case scenario. rTMS patients gained an average of 0.96 additional QALYs (equivalent to approximately 1 year in perfect health) over their lifetime with costs that were $46,094 less than ECT. rTMS remained dominant in the majority of scenario and threshold analyses. However, results from scenarios in which the model's maximum lifetime allowance of rTMS treatment courses was substantially limited, the dominance of rTMS over ECT was attenuated. The scenario that showed the highest QALY gain (1.19) and the greatest cost-savings ($46,614) was when rTMS nonresponders switched to ECT. From a societal perspective utilizing a lifetime horizon, rTMS is a cost-effective first-line treatment option for TRD relative to ECT, as it is less expensive and produces better health outcomes. The reduced side effect profile and greater patient acceptability of rTMS that allow it to be administered more times than ECT in a patient's lifetime may contribute to its cost-effectiveness.

Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor.

For many decades, glucocorticoids have been widely used as the gold standard treatment for inflammatory conditions. Unfortunately, their clinical use is limited by severe adverse effects such as insulin resistance, cardiometabolic diseases, muscle and skin atrophies, osteoporosis, and depression. Glucocorticoids exert their effects by binding to the Glucocorticoid Receptor (GR), a ligand-activated transcription factor which both positively, and negatively regulates gene expression. Extensive research during the past several years has uncovered novel mechanisms by which the GR activates and represses its target genes. Genome-wide studies and mouse models have provided valuable insight into the molecular mechanisms of inflammatory gene regulation by GR. This review focusses on newly identified target genes and GR co-regulators that are important for its anti-inflammatory effects in innate immune cells, as well as mutations within the GR itself that shed light on its transcriptional activity. This research progress will hopefully serve as the basis for the development of safer immune suppressants with reduced side effect profiles.

Abstract 4830: ABX9xx: A bispecific centyrin that synergizes to attenuate intracellular signaling in Met/EGFR positive tumors

Abstract ABX9xx is a bispecific Centyrin targeting the Met-EGFR axis, an emerging cancer treatment paradigm. Centyrins are small, chemically simple proteins based on a human FN3 domain that can be engineered to have high affinity for a selected target and are easily linked to form multi-specific binders. The standard of care for patients with EGFR mutant non-small cell lung cancer (NSCLC) is treatment with small molecule tyrosine kinase inhibitors (TKI) including recently approved third generation molecules (ie. osimertinib). Despite initial promising responses with TKIs, most patients regress within 12-14 months due to resistance. A predominant resistance mechanism dependent on Met amplification and signaling has been described from both in vitro experiments and clinical data. Targeting Met and EGFR with a bispecific ligand blocking inhibitor that attenuates intracellular signaling may provide a significant efficacy advantage and reduced side effect profile compared to small molecule TKI combinations. Exploiting the potential for avidity on tumor tissue, a bispecific ligand blocking inhibitor of Met and EGFRis also anticipated to provide improved selectivity for tumor tissue that overexpress both receptors compared to normal tissue with lower receptor expression. To enable sustained exposure while maintaining small size for good tumor penetration, ABX9xx includes a domain comprising an albumin binding Centyrin. ABX9xx activity on Met, EGFR and downstream signaling proteins was confirmed on several lung cancer cell lines in vitro including those carrying clinically observed mutations in Met and EGFR. ABX9xx inhibited EGFR phosphorylation independent of EGFR mutational status with higher potency than osimertinib. In addition, ABX9xx inhibited Met phosphorylation with higher potency than Crizotinib, an ALK inhibitor with cross reactivity to Met, currently used to treat Met positive patients. The pharmacokinetic properties of ABX9xx in animal models suggest a suitable dosing paradigm in patients. Together the data provides a strong rationale for advancing ABX9xx into clinical development for NSCLC and other cancers where EGFR and MET are drivers of tumor progression. Citation Format: Russ Addis, Robert Kolakowski, Swapnil Kulkarni, Josh Gorsky, Rebecca Meyer, Karyn ONeil. ABX9xx: A bispecific centyrin that synergizes to attenuate intracellular signaling in Met/EGFR positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4830.

Vitamin C supplementation expands the therapeutic window of BETi for triple negative breast cancer.

BackgroundBromodomain and extra-terminal inhibitors (BETi) have shown efficacy for the treatment of aggressive triple negative breast cancer (TNBC). However, BETi are plagued by a narrow therapeutic window as manifested by severe toxicities at effective doses. Therefore, it is a limitation to their clinical implementation in patient care.MethodsThe impact of vitamin C on the efficacy of small compounds including BETi was assessed by high-throughput screening. Co-treatment of TNBC by BETi especially JQ1 and vitamin C was evaluated in vitro and in vivo.FindingsHigh-throughput screening revealed that vitamin C improves the efficacy of a number of structurally-unrelated BETi including JQ1, I-BET762, I-BET151, and CPI-203 in treating TNBC cells. The synergy between BETi and vitamin C is due to suppressed histone acetylation (H3ac and H4ac), which is in turn caused by upregulated histone deacetylase 1 (HDAC1) expression upon vitamin C addition. Treatment with JQ1 at lower doses together with vitamin C induces apoptosis and inhibits the clonogenic ability of cultured TNBC cells. Oral vitamin C supplementation renders a sub-therapeutic dose of JQ1 able to inhibit human TNBC xenograft growth and metastasis in mice.InterpretationVitamin C expands the therapeutic window of BETi by sensitizing TNBC to BETi. Using vitamin C as a co-treatment, lower doses of BETi could be used to achieve an increased therapeutic index in patients, which will translate to a reduced side effect profile.FundUniversity of Miami Sylvester Comprehensive Cancer Center, Bankhead Coley Cancer Research program (7BC10), Flight Attendant Medical Research Institute, and NIH R21CA191668 (to GW) and 1R56AG061911 (to CW and CHV).

FRI-303-How to develop a differentiated FXR agonist: GS-9674 shows a reduced side effect profile in mice, monkeys amd human phase 1 studies compared to its predecessor Px-102

FRI-303-How to develop a differentiated FXR agonist: GS-9674 shows a reduced side effect profile in mice, monkeys amd human phase 1 studies compared to its predecessor Px-102

Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies

The ‘neurotrophic sesquiterpenes’ refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABAA receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other ‘cage convulsant’ compounds such as TETS and picrotoxin. We hypothesize that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.

Probing Angiotensin Converting Enzyme (ACE) Domain-Dependent Inhibition of Onopordia, Isolated from Onopordon acanthium L., Using a Continuous Fluorescent Assay

Background: Somatic ACE is a two-domain protein, C and N which are resulted from gene duplication. Presence of two active sites with particular properties, demonstrates functional significance of each domain. Increased levels of circulating N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), could be the result of ACE N-domain selective inhibition. Moreover, ACE C-domain specific inhibitors are able to inactivate bradykinin and inhibit the conversion of angiotensin I to angiotensin II in order to regulate blood pressure as well as reduced side effect profiles. Methods: The present study was designed to determine ACE domain specificity of the novel ACE inhibitor, onopordia which was recently isolated from Onopordon acanthium L. The ACE inhibition activity was determined using Abz-SDK (Dnp)P-OH and Abz-LFK(Dnp)-OH as ACE domain selective substrates. IC50 values of onopordia determined and compared with those of captopril as the standard. Results: IC50 values of onopordia for ACE N and C- domains were 180 µM and 244 µM respectively which demonstrated approximately similar affinity of the mentioned compound to ACE C and N-domains. A pharmacophore model was further generated based on onopordia interactions with the relevant ACE domain active sites. Conclusion: According to onopordia interactions in the ACE C and N-domain active sits, it is a potential to generate more potent and also specific inhibitor based on this new scaffold by doing accurate adjustments. Therefore, this study provides the molecular basis for further designing ACE inhibitors, which are new therapeutics in combating tissue fibrosis diseases.