Design of ultra-broadband absorption enhancement in plasmonic absorber by interaction resonance of multi-plasmon modes and Fabry-Perot mode.

This paper shows a strategy to realize ultra-broadband absorption of multi-spectral coverage. A vertical cascaded plasmonic absorber constructed by multilayer helical metallic nanostructure wrapped in a pyramid-shaped dielectric jacket is presented and investigated by numerical simulations. By premeditated planning of the scale proportions of the spirals and the dimension size of the pyramid-shaped dielectric, more than 90% of absorption is realized in 189-3896 nm, an ultra-wide spectral range that basically covers the bands of near-ultraviolet, visible light, and near-infrared. The excitation mechanism of electromagnetic resonance and the formation process of light trapping are both included in the investigation through the analysis of electromagnetic field distribution. The localized surface plasmon mode in the metallic nano-spiral and the Fabry-Perot cavity mode with the gap plasmon resonance in the dielectric gap cooperatively make a significant contribution to reduce the reflection and form the ultra-broadband absorption. The simulation results show that the proposed absorber is basically insensitive to the incident angle and polarization angle, which basically keeps more than 90% absorption within the incident angle of ± 80 °. Such a specific implementation idea can also be applied to the terahertz region by modifying the geometrical size of the structure. This presented design implies new viability to develop the broadband photodetectors, solar cells, and thermal emitters.

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer.

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

Divergent Synthesis of Revised Apratoxin E, 30-epi-Apratoxin E, and 30S/30R-Oxoapratoxin E.

In this report, originally proposed apratoxin E (30S-7), revised apratoxin E (30R-7), and (30S)/(30R)-oxoapratoxin E (30S)-38/(30R)-38 were efficiently prepared by two synthetic methods. The chiral lactone 10, recycled from the degradation of saponin glycosides, was utilized to prepare the key nonpeptide fragment 9. Our alternative convergent assembly strategy was applied to the divergent synthesis of revised apratoxin E and its three analogues. Moreover, ring-closing metathesis (RCM) was for the first time found to be an efficient strategy for the macrocyclization of apratoxins.

Asymmetric Synthesis of Apratoxin E.

An efficient method for asymmetric synthesis of apratoxin E 2 is described in this report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment 6. In addition to this "from nature to nature" strategy, olefin cross-metathesis (CM) was applied as an alternative approach for the formation of the double bond. Moreover, pentafluorophenyl diphenylphosphinate was found to be an efficient condensation reagent for the macrocyclization.

Divergent Method to trans-5-Hydroxy-6-alkynyl/alkenyl-2-piperidinones: Syntheses of (-)-Epiquinamide and (+)-Swainsonine.

An efficient diastereoselective approach to access trans-5-hydroxy-6-alkynyl/alkenyl-2-piperidinones has been developed through nucleophilic addition of α-chiral aldimines using alkynyl/alkenyl Grignard reagents. The diastereoselectivity of alkenyl in C-6 position of 2-piperidinone was controlled by α-alkoxy substitution, while the alkynyl was controlled by the coordination of the α-alkoxy substitution and stereochemistry of sulfinamide. The utility of this straightforward cascade process is demonstrated by the asymmetric synthesis of the (-)-epiquinamide and (+)-swainsonine.

Aging promotes the development of diet-induced murine steatohepatitis but not steatosis.

UNLABELLED: The prevalence of the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in humans increases with age. It is unknown whether this association is secondary to the increased incidence of risk factors for NAFLD that occurs with aging, reflects the culmination of years of exposure to lifestyle factors such as a high-fat diet (HFD), or results from physiological changes that characterize aging. To examine this question, the development of NAFLD in response to a fixed period of HFD feeding was examined in mice of different ages. Mice aged 2, 8, and 18 months were fed 16 weeks of a low-fat diet or HFD. Increased body mass and insulin insensitivity occurred in response to HFD feeding irrespective of the age of the mice. The amount of HFD-induced hepatic steatosis as determined biochemically and histologically was also equivalent among the three ages. Liver injury occurred exclusively in the two older ages as reflected by increased serum alanine aminotransferase levels, positive terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, and caspase activation. Older mice also had an elevated innate immune response with a more pronounced polarization of liver and adipose tissue macrophages into an M1 phenotype. Studies of cultured hepatocytes from young and old mice revealed that aged cells were selectively sensitized to the Fas death pathway. CONCLUSION: Aging does not promote the development of hepatic steatosis but leads to increased hepatocellular injury and inflammation that may be due in part to sensitization to the Fas death pathway and increased M1 macrophage polarization.

Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models.

PURPOSE: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed. EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI). RESULTS: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib. CONCLUSIONS: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.

Radical migration-addition of N-tert-butanesulfinyl imines with organozinc reagents.

A novel migration-addition sequence was discovered for the reaction of enantioenriched N-tert-butanesulfinyl iminoacetate 1a with functionalized benzylzinc bromide reagents, producing tert-leucine derivatives in excellent diastereoselectivity (dr 98:2). The absolute configurations of two new chiral centers were unambiguously assigned by chemical transformations and X-ray crystallography. In addition, the regio- and diastereoselectivities of this novel reaction were both explained through the key N-sulfinamine intermediate M6 generated by the tert-butyl radical attack on the imine. Computational analysis of this reaction process, which was performed at the B3LYP/6-311++G(3df,2p)//B3LYP/6-31G*-LANL2DZ level, also supported our proposed two-stage mechanism.

Diverse synthesis of marine cyclic depsipeptide lagunamide A and its analogues.

The asymmetric total synthesis of lagunamide A (3.0%, 20 steps longest linear sequence) and its five analogues, including the structure dehydrated at the C37 position, are detailed in this report. The key feature in this diverse synthesis includes the elaboration of four consecutive chiral centers at C37-40 and the final macrocyclization. Starting from chiral aldehyde 10, we synthesized both 1,3-anti and 1,3-syn homoallylic alcohols 20a and 20b through asymmetric aldol condensation and stereoselective allylation. The following esterification to introduce the L-N-Me-Ala unit resulted in significant epimerization. This problem was finally overcome by coupling the alcohols with the corresponding acid chloride of the L-alanine derivative. The key α,ß-unsaturated carboxylic acid unit was produced by cross-metathesis (CM) of methacrylaldehyde and related olefins. Interestingly, we found that the C7 configuration dramatically affected the ring closure. Natural lagunamide A (1a), its 39-epimer (1c), and its 2-epimer (1d) were obtained through macrolactamization between alanine and isoleucine moieties.

Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1.

The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.

Novel 6-aminofuro[3,2-c]pyridines as potent, orally efficacious inhibitors of cMET and RON kinases.

A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.

Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy.

Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model.

Imidazo[1,5-a]pyrazines: orally efficacious inhibitors of mTORC1 and mTORC2.

The discovery and optimization of a series of imidazo[1,5-a]pyrazine inhibitors of mTOR is described. HTS hits were optimized for potency, selectivity and metabolic stability to provide the orally bioavailable proof of concept compound 4c that demonstrated target inhibition in vivo and concomitant inhibition of tumor growth in an MDA-MB-231 xenograft model.

Evaluating Ligands for Ubiquitin Ligases Using Affinity Beads.

Proteolysis-targeting chimera (PROTAC®) protein degraders are heterobifunctional small molecules that bind a specific target protein on one end and a specific ubiquitin ligase enzyme (E3) on the other, thereby driving intracellular degradation of the target protein via the ubiquitin-proteasome system. PROTACs and other small molecule protein degraders are being developed as potential therapeutics for several diseases, with the first PROTACs having entered the clinic for cancer treatments in 2019. While humans express approximately 600 E3s, only a few have been used for protein degrader technology. A major challenge to designing degraders based on additional E3s is the development of quality ligands for other E3s. Most methods to screen for novel ligands employ purified forms of the protein of interest. Ligands discovered in this manner are typically subsequently evaluated in cultured cells. Optimal ligands efficiently cross biological membranes and interact specifically with the protein of interest, which can be assessed by a variety of cell-based methods. Functionality and specificity of ligand-protein interactions can also be evaluated using cell or tissue extracts and affinity beads based on the ligand, as described here. E3 affinity beads described herein are based on conjugation of the potential E3 ligand to biotin and commercially available streptavidin agarose with high affinity for biotin.

Glycogen synthase kinase 3 regulates PAX3-FKHR-mediated cell proliferation in human alveolar rhabdomyosarcoma cells.

Patients with alveolar rhabdomyosarcoma (ARMS) have poorer response to conventional chemotherapy and lower survival rates than those with embryonal RMS (ERMS). To identify compounds that preferentially block the growth of ARMS, we conducted a small-scale screen of 160 kinase inhibitors against the ARMS cell line Rh30 and ERMS cell line RD and identified inhibitors of glycogen synthase kinase 3 (GSK3), including TWS119 as ARMS-selective inhibitors. GSK3 inhibitors inhibited cell proliferation and induced apoptosis more effectively in Rh30 than RD cells. Ectopic expression of fusion protein PAX3-FKHR in RD cells significantly increased their sensitivity to TWS119. Down-regulation of GSK3 by GSK3 inhibitors or siRNA significantly reduced the transcriptional activity of PAX3-FKHR. These results suggest that GSK3 is directly involved in regulating the transcriptional activity of PAX3-FKHR. Also, GSK3 phosphorylated PAX3-FKHR in vitro, suggesting that GSK3 might regulate PAX3-FKHR activity via phosphorylation. These findings support a novel mechanism of PAX3-FKHR regulation by GSK3 and provide a novel strategy to develop GSK inhibitors as anti-ARMS therapies.

Flavonoids activate pregnane x receptor-mediated CYP3A4 gene expression by inhibiting cyclin-dependent kinases in HepG2 liver carcinoma cells.

BACKGROUND: The expression of the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is regulated by the pregnane x receptor (PXR), which is modulated by numerous signaling pathways, including the cyclin-dependent kinase (Cdk) pathway. Flavonoids, commonly consumed by humans as dietary constituents, have been shown to modulate various signaling pathways (e.g., inhibiting Cdks). Flavonoids have also been shown to induce CYPs expression, but the underlying mechanism of action is unknown. Here, we report the mechanism responsible for flavonoid-mediated PXR activation and CYP expression. RESULTS: In a cell-based screen designed to identify compounds that activate PXR-mediated CYP3A4 gene expression in HepG2 human carcinoma cells, we identified several flavonoids, such as luteolin and apigenin, as PXR activators. The flavonoids did not directly bind to PXR, suggesting that an alternative mechanism may be responsible for flavonoid-mediated PXR activation. Consistent with the Cdk5-inhibitory effect of flavonoids, Cdk5 and p35 (a non-cyclin regulatory subunit required to activate Cdk5) were expressed in HepG2. The activation of Cdk5 attenuated PXR-mediated CYP3A4 expression whereas its downregulation enhanced it. The Cdk5-mediated downregulation of CYP3A4 promoter activity was restored by flavonoids, suggesting that flavonoids activate PXR by inactivating Cdk5. In vitro kinase assays showed that Cdk5 directly phosphorylates PXR. The Cdk kinase profiling assay showed that apigenin inhibits multiple Cdks, suggesting that several Cdks may be involved in activation of PXR by flavonoids. CONCLUSIONS: Our results for the first time link the stimulatory effect of flavonoids on CYP expression to their inhibitory effect on Cdks, through a PXR-mediated mechanism. These results may have important implications on the pharmacokinetics of drugs co-administered with herbal remedy and herbal-drug interactions.

MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53.

Although the number of proteins effectively targeted for posttranslational degradation by PROTAC has grown steadily, the number of E3 ligases successfully exploited to accomplish this has been limited to the few for which small-molecule ligands have been discovered. Although the E3 ligase MDM2 is bound by the nutlin class of small-molecule ligands, there are few nutlin-based PROTAC. Because a nutlin-based PROTAC should both knockdown its target protein and upregulate the tumor suppressor p53, we examined the ability of such a PROTAC to decrease cancer cell viability. A nutlin-based, BRD4-degrading PROTAC, A1874, was able to degrade its target protein by 98% with nanomolar potency. Given the complementary ability of A1874 to stabilize p53, we discovered that the nutlin-based PROTAC was more effective in inhibiting proliferation of many cancer cell lines with wild-type p53 than was a corresponding VHL-utilizing PROTAC with similar potency and efficacy to degrade BRD4. This is the first report of a PROTAC in which the E3 ligase ligand and targeting warhead combine to exert a synergistic antiproliferative effect. Our study highlights the untapped potential that may be unlocked by expanding the repertoire of E3 ligases that can be recruited by PROTAC. SIGNIFICANCE: These findings present the first BRD4-targeting MDM2-based PROTAC that possesses potent, distinct, and synergistic biological activities associated with both ends of this heterobifunctional molecule.

Highly Enantioselective Rhodium-Catalyzed Cross-Addition of Silylacetylenes to Cyclohexadienone-Tethered Internal Alkynes.

The first highly enantioselective rhodium-catalyzed cross-addition of silylacetylenes to cyclohexadienone-tethered internal alkynes has been achieved via a tandem process: regioselective alkynylation of the internal alkynes and subsequent intramolecular conjugate addition to the cyclohexadienones, affording the cis-hydrobenzofuran frameworks with good yields (up to 88% yield) and excellent enantioselectivities (90%-96% ee). This mild reaction showed perfect atom economy and broad functional group tolerance. Furthermore, a gram-scale experiment and diverse further conversions of the cyclization products were also presented.

Poly-ICLC, a TLR3 Agonist, Induces Transient Innate Immune Responses in Patients With Treated HIV-Infection: A Randomized Double-Blinded Placebo Controlled Trial.

Objective: Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. Design: This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants (n = 15) were randomized 3:1 to receive two consecutive daily doses of Poly-ICLC (1.4 mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Methods: Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4+ T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Results: Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4+ T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. Conclusions: These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV+ subjects indicating promise as an adjuvant for HIV therapeutic vaccines. Trial Registration: www.ClinicalTrials.gov, identifier: NCT02071095.