Potent Selective Inhibitor Research Articles

Renieramycin T Induces Lung Cancer Cell Apoptosis by Targeting Mcl-1 Degradation: A New Insight in the Mechanism of Action.

Among malignancies, lung cancer is the major cause of cancer death. Despite the advance in lung cancer therapy, the five-year survival rate is extremely restricted due to therapeutic failure and disease relapse. Targeted therapies selectively inhibiting certain molecules in cancer cells have been accepted as promising ways to control cancer. In lung cancer, evidence has suggested that the myeloid cell leukemia 1 (Mcl-1) protein, an anti-apoptotic member of the Bcl-2 family, is a target for drug action. Herein, we report the Mcl-1 targeting activity of renieramycin T (RT), a marine-derived tetrahydroisoquinoline alkaloid that was isolated from the Thai blue sponge Xestospongia sp. RT was shown to be dominantly toxic to lung cancer cells compared to the normal cells in the lung. The cytotoxicity of this compound toward lung cancer cells was mainly exerted through apoptosis induction. For the mechanism of action, we found that RT mediated activation of p53 protein and caspase-9 and -3 activations. While others Bcl-2 family proteins (Bcl-2, Bak, and Bax) were minimally changed in response to RT, Mcl-1 protein was dramatically diminished. We further performed the cycloheximide experiment and found that the half-life of Mcl-1 was significantly shortened by RT treatment. When MG132, a potent selective proteasome inhibitor, was utilized, it could restore the Mcl-1 level. Furthermore, immunoprecipitation analysis revealed that RT significantly increased the formation of Mcl-1-ubiquitin complex compared to the non-treated control. In conclusion, we report the potential apoptosis induction of RT with a mechanism of action involving the targeting of Mcl-1 for ubiquitin-proteasomal degradation. As Mcl-1 is critical for cancer cell survival and chemotherapeutic failure, this novel information regarding the Mcl-1-targeted compound would be beneficial for the development of efficient anti-cancer strategies or targeted therapies.

Efficacy of a novel potent and high water-soluble selective PARP inhibitor CVL218 in glioma.

e13539 Background: Glioma is the most common, deadly, and difficult-to-treat intracranial tumor. Up to 70% of gliomas are found to carry isocitrate dehydrogenase (IDH) mutations, which induce a homologous recombination defect (HRD) that renders glioma cells sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi). However, 4 launched PARPi have limitation for IDH-mutant glioma because of low concentration level in brain. CVL218 is a novel potent and high water-soluble selective PARP-1/2 inhibitor. Pharmacokinetic studies in rats showed that CVL218 can easily across the BBB, has 10 times higher concentration in brain than in the plasma, indicating its therapeutic potential in glioma. Here, we examined its effect on glioma in vitro and in vivo. Methods: BT142 mut/- glioma cells with a homozygous IDH1 R132H mutation were exploited. Chemotherapeutic agent temozolomide (TMZ), PARPi Olaparib and Niraparib, were used as controls. The inhibition of BT142 cell growth by compounds in vitro was measured by MTT assay. Female NOD/SCID mice with orthotopic xenografts of BT142 glioma cells were used to evaluate the antitumor efficacy of compounds in vivo. Medium survival time (MST) was compared using the Kaplan-Meier method and logrank test. Results: CVL218 inhibited the BT142 cell growth in vitro with an IC50 of 2.07 ± 0.62 μM, better than Olaparib and Niraparib. Orthotopic xenograft glioma mice model study showed that CVL218 group significantly extended the MST to 98.0 days ( p= 0.0206), while MST of TMZ treated group is 85.0 days. Conclusions: CVL218 inhibits IDH1-mutant BT142 glioma cell growth in vitro and in vivo. The present findings suggest that CVL218 is a potential agent which could be useful as a treatment for IDH-mutant glioma. We will start its phase I clinical study for glioma soon.

Phase I trial of IACS-010759 (IACS), a potent, selective inhibitor of complex I of the mitochondrial electron transport chain, in patients (pts) with advanced solid tumors.

3014 Background: A subset of tumors possess genetic or microenvironmental alterations that render cells dependent on mitochondria oxidative phosphorylation (OXPHOS) for survival. IACS, a potent oral selective inhibitor of mitochondrial complex I, showed robust responses in multiple preclinical tumor models, providing strong rationale for clinical testing. Methods: Pts with advanced cancers received IACS in increasing dose levels (DL) using 3+3 dose escalation. 7-day QD induction of IACS was followed by maintenance weekly (QW) or twice weekly (BIW) dosing. Phamacokinetics (PK), lactate and pH were assessed serially. Paired tumor biopsies were assessed for pharmacodynamic and predictive biomarkers. Results: 18 pts were treated; M/F 16/2; ECOG PS 0/1: 3/15. Mean age 49 (23-69) yrs. Tumors comprised advanced colorectal (n = 4), castration resistant prostate cancer (CRPC) (n = 3), pancreatic (n = 2), other cancers (n = 9). DL1: 2mg QD 7 days induction/0.5mg QW maintenance (n = 3); DL2: 2.5mg QD 7 days/1mg QW (n = 3); DL3: 3mg QD 7 days/3mg QW (n = 3); DL4: 2.5mg QD 7 days/2.5mg BIW (n = 4); DL5: 2mg QD 7 days/2mg BIW (n = 5). IACS was well tolerated with 12 (67%) pts reporting G1-2 IACS related toxicities, such as raised lactate (n = 10), nausea (n = 8), fatigue (n = 7), vomiting (n = 5), myalgia (n = 4) and peripheral neuropathy (n = 4). 1 pt in DL3 and 2 pts in DL4 had ≥G3 IACS related toxicities, such as nausea (n = 2), vomiting (n = 1), raised lactate (n = 1), dehydration (n = 1), visual changes (n = 1), and peripheral neuropathy (n = 1). Raised lactate was not associated with acidosis. DL5 is now being expanded to assess the maximum tolerated dose (MTD). PK showed good oral bioavailability, with long T1/2 and low intrapatient variability. Cmax = 14nM on Day 7 at the end of DL5 induction phase, confirming biologically active doses. 7 pts had best response of RECIST stable disease. A pt with heavily pretreated CRPC achieved RECIST partial response with resolution of CRPC related pain. Conclusions: IACS is well tolerated with preliminary evidence of antitumor activity. MTD expansions include CRPC, TNBC, pancreatic cancer and molecularly selected (ENO1 loss; SMARCA4 mutation) tumor cohorts. Clinical trial information: NCT03291938.

Novel 7-formyl-naphthyridyl-ureas derivatives as potential selective FGFR4 inhibitors: Design, synthesis, and biological activity studies.

Total twenty-five 7-formyl-naphthyridyl-urea derivatives were designed, synthesized and evaluated for their inhibition of FGFR4 kinase and antitumor activity. The pharmacological data indicated that most of the tested compounds showed high selectivity towards FGFR4 kinase and could significantly inhibit FGFR4 and the tumor cells lines with the high expression of FGFR4. In particular, compounds 6f, 6g, 6h, 6l, 6m and 6s showed a good performance in pharmacokinetic tests. When tested in mice, the representative compound 6f was found to have good pharmacokinetic parameters, low toxicity, and better tumor inhibiting activity in vivo.

Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors

PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.

Identification of novel monoamine oxidase selective inhibitors employing a hierarchical ligand-based virtual screening strategy.

Aim: Due to the pivotal role in the oxidative deamination of monoamine neurotransmitters, two distinct monoamine oxidase (MAO) subtypes, MAO-A and MAO-B, present a significant pharmacological interest. Here, we reported a hierarchical and time-efficient ligand-based virtual screening strategy to identify potent selective and reversible MAO inhibitors. Result: A total of 130 compounds were assessed in dose-response biochemical assay against MAOs. Among them, 70 compounds were active with inhibition higher than 70%, involving 25 compounds with IC50 values less than 1μM. Conclusion: Our research demonstrated the validity of Biologically Relevant Spectrum (BRS-3D) in predicting subtype-selective ligands and afforded a novel highly efficient way to develop selective inhibitors in the early stage of drug discovery.

Germ Cell Apoptosis and Oxidative DNA Damage in Testicular Ischemia Reperfusion Injury: Survivin’ the Lipoxygenases

ObjectiveTesticular ischemia reperfusion injury (tIRI) is widely accepted as the underlying mechanism for the pathophysiology of testicular torsion and detrorsion (TTD) in young children that could increase the risk of male infertility. The aim of this study is to examine the role of the pro‐oxidative lipoxygenases (LOXs)‐induced testicular oxidative stress in the etiology of tIRI‐induced germ cell apoptosis (GCA) and oxidative DNA damage using its potent selective inhibitor nordihydroguaiaretic acid (NDGA).Materials and methodsSprague‐Dawley male rats (n = 36, 8 weeks old, 250–300g) were randomly assigned to three groups: Sham, unilateral tIRI and tIRI + NDGA (25 mg/kg). Rats underwent 1 hour ischemia followed by 4 hours reperfusion. Harvested testes were evaluated for spermatogenic damage by H&E staining, oxidative DNA damage by biochemical assays, GCA, and tissue immunoexpression of the three LOXs (LOX‐5, ‐12 and ‐15). The induction of GCA and the involvement of the apoptosis pathways survivin/ASK‐1/JNK and was investigated by immunofluorescence staining.ResultsOur data showed that tIRI caused disorganization of the seminiferous tubules layers and significant spermatogenic damage. Increased LOX immunoexpression but not mRNA expression was calculated as a result of tIRI. Augmented levels of LOX‐induced protein, lipid, and DNA oxidative damage were significantly elevated during tIRI. In addition, tIRI activated the ASK‐1/JNK signaling pathway, which was associated with the down regulation of survivin, an inhibitor of apoptosis. Selective inhibition of LOXs by NDGA diminished the above tIRI‐induced changes.ConclusionThe study outcomes implicates the role of LOXs in the generation of reactive oxygen species, which partly contributed to the tIRI‐induced oxidative damage that also led to spermatogenic damage, oxidative DNA damage and induction of the apoptosis pathway survivin/ASK‐1/JNK. This new finding provides a good understanding to the tIRI/TTD mechanism in the field of translational medicine worldwide.Support or Funding InformationKuwait Foundation for the Advancement of Science (KFAS), Kuwait – Project Code: P116‐13MB‐01.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Design, synthesis, in vivo and in vitro studies of 1,2,3,4-tetrahydro-9H-carbazole derivatives, highly selective and potent butyrylcholinesterase inhibitors.

Inhibition of butyrylcholinesterase (BChE) might be a useful therapeutic target for Alzheimer's disease (AD). A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit (> 100µM), they were selective potent BChE inhibitors. 1-(2-(6-fluoro-1,2,3,4-tetrahydro-9H-carbazole-9-yl)ethyl)piperidin-1-ium chloride (15g) had the most potent anti-BChE activity (IC50 value = 0.11μM), the highest BChE selectivity and mixed-type inhibition. Pharmacokinetic properties were accordant to Lipinski rule and compound 15g demonstrated neuroprotective and inhibition of β-secretase (BACE1) activities. Furthermore, in vivo study of compound 15g in Morris water maze task has confirmed memory improvement in scopolamine-induced impairment. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD. A new series of 1,2,3,4-tetrahydro-9H-carbazole derivatives were designed synthesized and evaluated as BChE inhibitors. While all of the derivatives have shown for AChE IC50 values below the detectable limit, they were selective potent BChE inhibitors. Compound 15g had the most potent anti-BChE activity. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.

Binding pocket-based design, synthesis and biological evaluation of novel selective BRD4-BD1 inhibitors.

Bromodomain-containing protein 4 (BRD4), consisting of two tandem bromodomains (BD1 and BD2), is key epigenetic regulator in fibrosis and cancer, which has been reported that BD1 and BD2 have distinct roles in post-translational modification. But there are few selective inhibitors toward those two domains. Herein, this study designed and synthesized a series of novel selective BRD4-BD1 inhibitors, using computer-aided drug design (CADD) approach focused on exploring the difference of the binding pockets of BD1 and BD2, and finding the His437 a crucial way to achieve BRD4-BD1 selectivity. Our results revealed that the compound 3u is a potent selective BRD4-BD1 inhibitor with IC50 values of 0.56 μM for BD1 but >100 μM for BD2. The compound exhibited a broad spectrum of anti-proliferative activity against several human cancer and fibroblastic cell lines, which might be related to its capability of reducing the expression of c-Myc and collagen I. Furthermore, it could induce apoptosis in A375 cells. To the contrary, the selective BD2 inhibitor, RVX-208, did not indicate any of these activities. Our findings highlight that the function of BRD4-BD1 might be predominant in fibrosis and cancer. And it is rational to further develop novel selective BRD4-BD1 inhibitors.

Novel benzenesulfonamide and 1,2-benzisothiazol-3(2H)-one-1,1-dioxide derivatives as potential selective COX-2 inhibitors

Two new series of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide derivatives containing either five membered heterocyclic rings or aryl hydrazones were synthesized and evaluated for their in vitro COX-1/COX-2 inhibitory activity. In vivo anti-inflammatory evaluation revealed that benzenesulfonamides bearing pyrazole moiety 19, 20 and its cyclized form 23 exhibited the highest anti-inflammatory activity with comparable potency to celecoxib. Furthermore, the ulcerogenic activity evaluation showed that compounds 19, 20 and 23 exerted the minimal ulcer index in comparison to indomethacin as a reference drug. Docking studies of the most selective COX-2 derivatives were also carried out against COX-2 active site. Benzenesulfonamide derivatives 19 and 20 displayed higher predicted binding affinities inside the COX-2 active site. Molecular modelling simulation and drug likeness studies showed good agreement with the obtained biological evaluation.

Discovery of Novel Bromophenol-Thiosemicarbazone Hybrids as Potent Selective Inhibitors of Poly(ADP-ribose) Polymerase-1 (PARP-1) for Use in Cancer.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a new potential target for anticancer drug discovery. A series of bromophenol-thiosemicarbazone hybrids as PARP-1 inhibitors were designed, synthesized, and evaluated for their antitumor activities. Among them, the most promising compound, 11, showed excellent selective PARP-1 inhibitory activity (IC50 = 29.5 nM) over PARP-2 (IC50 > 1000 nM) and potent anticancer activities toward the SK-OV-3, Bel-7402 and HepG2 cancer cell lines (IC50 = 2.39, 5.45, and 4.60 μM), along with inhibition of tumor growth in an in vivo SK-OV-3 cell xenograft model. Further study demonstrated that compound 11 played an antitumor role through multiple anticancer mechanisms, including the induction of apoptosis and cell cycle arrest, cellular accumulation of DNA double-strand breaks, DNA repair alterations, inhibition of H2O2-triggered PARylation, antiproliferative effects via the production of cytotoxic reactive oxygen species, and autophagy. In addition, compound 11 displayed good pharmacokinetic characteristics and favorable safety. These observations demonstrate that compound 11 may serve as a lead compound for the discovery of new anticancer drugs.

TGN-020 alleviates edema and inhibits astrocyte activation and glial scar formation after spinal cord compression injury in rats

AimsIdentifying drugs that inhibit edema and glial scar formation and increase neuronal survival is crucial to improving outcomes after spinal cord injury (SCI). Here, we used 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a potent selective inhibitor of aquaporin 4 (AQP4), to investigate the effects of TGN-020 on SCI in Sprague-Dawley rats. Main methodsWe compressed the spinal cord at T10 using a sterile impounder (35 g, 5 min), to induce moderate injury. TGN-020 (100 mg/kg) or an equal volume of 10% dimethyl sulfoxide was then administered via intraperitoneal injection. Neurological function was evaluated using the Basso-Beattie-Bresnahan open-field locomotor scale 1, 3, 7, 14, 21, and 28 days after SCI. The degree of edema was assessed via determination of the precise spinal cord water content 3 days after SCI. Expression levels of AQP4, glial fibrillary acidic protein (GFAP), proliferating cell nuclear antigen (PCNA), and growth-associated protein-43 (GAP-43) were determined via western blotting and immunofluorescence staining 3 days after SCI and 4 weeks after SCI. Numbers of surviving neurons and glial scar sizes were determined using Nissl and hematoxylin-eosin staining, respectively. Key findingsOur results showed that TGN-020 promoted functional recovery at days 3, 7, 14, 21, and 28, as well as reduced the degree of edema and inhibited the expression of AQP4, GFAP, PCNA at days 3 after SCI. Furthermore, observations 4 weeks after SCI revealed that TGN-020 inhibited the glial scar formation and upregulated GAP-43 expression. SignificanceTGN-020 can alleviate spinal cord edema, inhibit glial scar formation, and promote axonal regeneration, conferring beneficial effects on recovery in rats.

Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation.

Many human neurodegenerative diseases are associated with amyloid fibril formation. Inhibition of amyloid formation is of importance for therapeutics of the related diseases. However, the development of selective potent amyloid inhibitors remains challenging. Here based on the structures of amyloid β (Aβ) fibrils and their amyloid-forming segments, we designed a series of peptide inhibitors using RosettaDesign. We further utilized a chemical scaffold to constrain the designed peptides into β-strand conformation, which significantly improves the potency of the inhibitors against Aβ aggregation and toxicity. Furthermore, we show that by targeting different Aβ segments, the designed peptide inhibitors can selectively recognize different species of Aβ. Our study developed an approach that combines the structure-based rational design with chemical modification for the development of amyloid inhibitors, which could be applied to the development of therapeutics for different amyloid-related diseases.

Selective Inhibition of Human Monoamine Oxidase B by Acacetin 7-Methyl Ether Isolated from Turnera diffusa (Damiana).

The investigation of the constituents that were isolated from Turnera diffusa (damiana) for their inhibitory activities against recombinant human monoamine oxidases (MAO-A and MAO-B) in vitro identified acacetin 7-methyl ether as a potent selective inhibitor of MAO-B (IC50 = 198 nM). Acacetin 7-methyl ether (also known as 5-hydroxy-4′, 7-dimethoxyflavone) is a naturally occurring flavone that is present in many plants and vegetables. Acacetin 7-methyl ether was four-fold less potent as an inhibitor of MAO-B when compared to acacetin (IC50 = 50 nM). However, acacetin 7-methyl ether was >500-fold selective against MAO-B over MAO-A as compared to only two-fold selectivity shown by acacetin. Even though the IC50 for inhibition of MAO-B by acacetin 7-methyl ether was ~four-fold higher than that of the standard drug deprenyl (i.e., SelegilineTM or ZelaparTM, a selective MAO-B inhibitor), acacetin 7-methyl ether’s selectivity for MAO-B over MAO-A inhibition was greater than that of deprenyl (>500- vs. 450-fold). The binding of acacetin 7-methyl ether to MAO-B was reversible and time-independent, as revealed by enzyme-inhibitor complex equilibrium dialysis assays. The investigation on the enzyme inhibition-kinetics analysis with varying concentrations of acacetin 7-methyl ether and the substrate (kynuramine) suggested a competitive mechanism of inhibition of MAO-B by acacetin 7-methyl ether with Ki value of 45 nM. The docking scores and binding-free energies of acacetin 7-methyl ether to the X-ray crystal structures of MAO-A and MAO-B confirmed the selectivity of binding of this molecule to MAO-B over MAO-A. In addition, molecular dynamics results also revealed that acacetin 7-methyl ether formed a stable and strong complex with MAO-B. The selective inhibition of MAO-B suggests further investigations on acacetin 7-methyl as a potential new drug lead for the treatment of neurodegenerative disorders, including Parkinson’s disease.

Discovery of (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide as potent and isoform selective ROCK2 inhibitors.

ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biologically evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC50 value of 3 nM and 22.7-fold isoform selectivity (vs. ROCK1). Molecular docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the experimental bioactivities, and the analysis of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.

Homology modeling of human histone deacetylase 10 and design of potential selective inhibitors

Histone deacetylases (HDACs) are implicated in the pathology of various cancers, and their pharmacological blockade has proven to be promising in reversing the malignant phenotypes. However, lack of crystal structures of some of the human HDAC isoforms (e.g., HDAC10) hinders the design of the isoform-selective inhibitor. Here, the recently solved X-ray crystal structure of Danio rerio (zebrafish) HDAC10 (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) was retrieved from the PDB and used as a template structure to model the three-dimensional structure of human HDAC10. The overall quality of the best model (M0017) was assessed by computing its z-score—a measure of the deviation of the total energy of the structure with respect to an energy distribution derived from random conformations and by docking of known HDAC10 inhibitors to its catalytic cavity. Furthermore, to identify potential HDAC10-selective inhibitor ligand-based virtual screening was carried out against the ZINC database. The free modeled structure of HDAC10 and its complexes with quisinostat and the highest-ranked compound ZINC19749069 were submitted to molecular dynamics simulation. The comparative analysis of root-mean-squared deviation, root-mean-squared fluctuation, radius of gyration (Rg), and potential energy of these systems showed that HDAC10-ZINC19749069 complex remained the most stable over time. Thus, M0017 could be potentially used for structure-based inhibitor against HDAC10, and ZINC19749069 may provide a scaffold for further optimization.Communicated by Ramaswamy H. Sarma

Brain-derived neurotrophic factor: A steroidogenic regulator of Leydig cells.

The brain-derived neurotrophic factor (BDNF) was first recognized for its roles in the peripheral and central nervous systems, and its complex functions on mammalian organs have been extended constantly. However, to date, little is known about its effects on the male reproductive system, including the steroidogenesis of mammals. The purpose of this study was to elucidate the effects of BDNF on testosterone generation of Leydig cells and the underlying mechanisms. We found that BDNF-induced proliferation of TM3 Leydig cells via upregulation of proliferating cell nuclear antigen ( Pcna) and promoted testosterone generation as a result of upregulation of steroidogenic acute regulatory protein ( Star), 3b-hydroxysteroid dehydrogenase ( Hsd3b1), and cytochrome P450 side-chain cleavage enzyme ( Cyp11a1) both in primary Leydig cells and TM3 Leydig cells, which were all attenuated in Bdnf knockdown TM3 Leydig cells. Furthermore, the possible mechanism of testosterone synthesis was explored in TM3 Leydig cells. The results showed that BDNF enhanced extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation, and the effect was disrupted by Bdnf deletion. Moreover, PD98059, a potent selective inhibitor of ERK1/2 activation, compromised BDNF-induced testosterone generation and upregulation of Star, Hsd3b1, and Cyp11a1. The Bdnf knockdown assay, on the other hand, indicated the autocrine effect of BDNF on steroidogenesis in TM3 Leydig cells. On the basis of these results, we concluded that BDNF, acting as an autocrine factor, induced testosterone generation as a result of the upregulation of Star, Hsd3b1, and Cyp11a1 via stimulation of the ERK1/2 pathway.

Structure-Based Discovery of a Subtype-Selective Inhibitor Targeting a Transient Receptor Potential Vanilloid Channel.

Discovery of potent selective inhibitors targeting a protein from a highly conserved family is challenging. Using a strategy combining structural and evolutionary information, we discovered transient receptor potential (TRP) subtype-selective inhibitors (transient receptor potential vanilloid type 2 (TRPV2) inhibitors). We unveiled three ligand-binding sites of TRPV2 and compounds that bind to these sites. Structural optimization of the best-hit compound provided a potent selective TRPV2 inhibitor, SET2. The molecular basis and subtype-selective inhibition mechanism were quantitatively characterized and experimentally verified. Then, as an effective chemical probe, SET2 was used to investigate the function role of TRPV2. SET2-induced inhibition of TRPV2 reduced prostate cancer migration, which indicated TRPV2 as an antimetastasis therapeutic target. In addition, functional assays suggested that TRPV2 was coupled to a validated metastasis mediator, LPAR1. The discovery of the potent selective inhibitor potentially leads to novel avenues for pharmacological applications and therapeutic development targeting the TRPV2 channel.

Discovery, synthesis and anti-atherosclerotic activities of a novel selective sphingomyelin synthase 2 inhibitor

The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 μM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.

Overview of idelalisib for pharmacists

AbstractIdelalisib is a potent oral selective inhibitor of phosphatidylinositol 3‐kinase p110δ. It is approved in Australia for the treatment of relapsed chronic lymphocytic leukaemia and small cell lymphocytic lymphoma in combination with rituximab or ofatumumab in patients for whom chemoimmunotherapy is not considered suitable. Idelalisib is reimbursed by the Australian Government for use in combination with rituximab. It is also approved and reimbursed for use as monotherapy in patients with follicular lymphoma refractory to at least two prior systemic therapies including rituximab and an alkylating agent. Idelalisib has demonstrated significant benefits in progression‐free survival and overall survival in these patient populations; however, patients receiving idelalisib require monitoring and education due to significant toxicities, particularly diarrhoea, infections and hepatotoxicity. There is also the potential for drug interactions resulting in toxicity or subtherapeutic treatment levels.