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Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N -unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

The virally encoded 3C-like protease (3CL pro ) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CL pro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CL pro in SARS-CoV-2 virus is described herein., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The 1,3-dihydro-2 H -benzo[ d ]azepin-2-ones are potent and ligand-efficient pan-BET bromodomain inhibitors. Here we describe the extension of this template to exploit a bivalent mode of action, binding simultaneously to both bromodomains. Initially the linker length and attachment vectors compatible with bivalent binding were explored, leading to the discovery of exceptionally potent bivalent BET inhibitors within druglike rule-of-5 space., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Background/aim: The therapeutic potential of bromodomain and extra-terminal motif (BET) inhibitors in hematological cancers has been well established in preclinical and early-stage clinical trials, although as of yet, no BETtargeting agent has achieved approval. To add insight into potential response to mivebresib (ABBV-075), a broadspectrum BET inhibitor, co-clinical modeling of individual patient biopsies was conducted in the context of a Phase I trial in acute myeloid leukemia (AML)., Materials and Methods: Co-clinical modeling involves taking the patient's biopsy and implanting it in mice with limited passage so that it closely retains the original characteristics of the malignancy and allows comparisons of response between animal model and clinical data. Procedures were developed, initially with neonate NOD/Shi-scid-IL2rγnull (NOG) mice and then optimized with juvenile NOG-EXL as host mice, eventually resulting in a robust rate of engraftment (16 out of 26, 62%)., Results: Results from the co-clinical AML patient-derived xenograft (PDX) modeling (6 with >60% inhibition of bone marrow blasts) were consistent with the equivalent clinical data from patients receiving mivebresib in monotherapy, and in combination with venetoclax. The modeling system also demonstrated the activity of a novel BD2-selective BET inhibitor (ABBV-744) in the preclinical AML setting. Both agents were also highly effective in inhibiting blast counts in the spleen (10/10 and 5/6 models, respectively)., Conclusion: These findings confirm the validity of the model system in the co-clinical setting, establish highly relevant in vivo models for the discovery of cancer therapy, and indicate the therapeutic value of BET inhibitors for AML and, potentially, myelofibrosis treatment., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Over the past two decades, Factor XIa inhibitors have emerged as an exciting new class of antithrombic agents. Identification of orally bioavailable small molecule inhibitors has presented a formidable challenge for medicinal chemists. Herein, those challenges and the problem-solving that resulted in the discovery of milvexian will be presented.

Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins. In contrast to the broad antiproliferative activities observed with dual bromodomain BET inhibitors, ABBV-744 displayed significant antiproliferative activities largely although not exclusively in cancer cell lines derived from acute myeloid leukemia and androgen receptor positive prostate cancer. Studies in acute myeloid leukemia xenograft models demonstrated antitumor efficacy for ABBV-744 that was comparable with the pan-BET inhibitor ABBV-075 but with an improved therapeutic index. Enhanced antitumor efficacy was also observed with the combination of ABBV-744 and the BCL-2 inhibitor, venetoclax compared with monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006)., (©2021 American Association for Cancer Research.)

Piperazine-containing compounds serve as one of the most important classes of compounds throughout all fields of chemistry. Alas, current synthetic methods have fallen short of providing a general method for the synthesis of highly decorated piperazine fragments. Herein, we present a site-selective approach to the C-H functionalization of existing piperazine compounds using photoredox catalysis. This manifold relies on the predictable differentiation of electronically distinct nitrogen centers within the piperazine framework, granting access to novel C-alkylated variants of the starting piperazines.

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR)., Methods: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors., Results: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts., Conclusion: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3-SMARCA4-miR-27a-PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Hematotoxicity is a life-threatening side effect of many chemotherapy regimens. Although clinical factors influence patient responses, genetic factors may also play an important role. We sought to identify genomic loci that influence chemotherapy-induced hematotoxicity by dosing Diversity Outbred mice with one of three chemotherapy drugs; doxorubicin, cyclophosphamide or docetaxel. We observed that each drug had a distinct effect on both the changes in blood cell subpopulations and the underlying genetic architecture of hematotoxicity. For doxorubicin, we mapped the change in cell counts before and after dosing and found that alleles of ATP-binding cassette B1B (Abcb1b) on chromosome 5 influence all cell populations. For cyclophosphamide and docetaxel, we found that each cell population was influenced by distinct loci, none of which overlapped between drugs. These results suggest that susceptibility to chemotherapy-induced hematotoxicity is influenced by different genes for different chemotherapy drugs.

Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models minimal information standard (PDX-MI) for reporting on the generation, quality assurance, and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient's tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use of PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models. Cancer Res; 77(21); e62-66. ©2017 AACR ., (©2017 American Association for Cancer Research.)

LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad lib-fed mice. Further, treating mice with LX2761 and the dipeptidyl-peptidase 4 inhibitor sitagliptin synergistically increased active GLP-1 levels, suggesting increased LX2761-mediated release of GLP-1 into the portal circulation. LX2761 also lowered postprandial glucose, fasting glucose, and hemoglobin A1C, and increased plasma total GLP-1, during long-term treatment of mice with either early- or late-onset streptozotocin-diabetes; in the late-onset cohort, LX2761 treatment improved survival. Mice and rats treated with LX2761 occasionally had diarrhea; this dose-dependent side effect decreased in severity and frequency over time, and LX2761 doses were identified that decreased postprandial glucose excursions without causing diarrhea. Further, the frequency of LX2761-associated diarrhea was greatly decreased in mice either by gradual dose escalation or by pretreatment with resistant starch 4, which is slowly digested to glucose in the colon, a process that primes the colon for glucose metabolism by selecting for glucose-fermenting bacterial species. These data suggest that clinical trials are warranted to determine if LX2761 doses and dosing strategies exist that provide improved glycemic control combined with adequate gastrointestinal tolerability in people living with diabetes., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.

Increased histone deacetylase (HDAC) activity and the resulting dysregulation of protein acetylation is an integral event in retinal degenerations associated with ischemia and ocular hypertension. This study investigates the role of preconditioning on the process of acetylation in ischemic retinal injury. Rat eyes were unilaterally subjected to retinal injury by 45 min of acute ischemia, and retinal neuroprotection induced by 5 min of an ischemic preconditioning (IPC) event. HDAC activity was evaluated by a fluorometric enzymatic assay with selective isoform inhibitors. Retinal localization of acetylated histone-H3 was determined by immunohistochemistry on retina cross sections. Cleaved caspase-3 level was evaluated by Western blots. Electroretinogram (ERG) analyses were used to assess differences in retinal function seven days following ischemic injury. In control eyes, analysis of HDAC isoforms demonstrated that HDAC1/2 accounted for 28.4 ± 1.6%, HDAC3 for 42.4 ± 1.5% and HDAC6 activity 27.3 ± 3.5% of total activity. Following ischemia, total Class-I HDAC activity increased by 21.2 ± 6.2%, and this increase resulted solely from a rise in HDAC1/2 activity. No change in HDAC3 activity was measured. Activity of Class-II HDACs and HDAC8 was negligible. IPC stimulus prior to ischemic injury also suppressed the rise in Class-I HDAC activity, cleaved caspase-3 levels, and increased acetylated histone-H3 in the retina. In control animals 7 days post ischemia, ERG a- and b-wave amplitudes were significantly reduced by 34.9 ± 3.1% and 42.4 ± 6.3%, respectively. In rats receiving an IPC stimulus, the ischemia-induced decline in ERG a- and b-wave amplitudes was blocked. Although multiple HDACs were detected in the retina, these studies provide evidence that hypoacetylation associated with ischemic injury results from the selective rise in HDAC1/2 activity and that neuroprotection induced by IPC is mediated in part by suppressing HDAC activity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Targeting tumor-overexpressed EGFR with an antibody-drug conjugate (ADC) is an attractive therapeutic strategy; however, normal tissue expression represents a significant toxicity risk. The anti-EGFR antibody ABT-806 targets a unique tumor-specific epitope and exhibits minimal reactivity to EGFR in normal tissue, suggesting its suitability for the development of an ADC. We describe the binding properties and preclinical activity of ABT-414, an ABT-806 monomethyl auristatin F conjugate. In vitro, ABT-414 selectively kills tumor cells overexpressing wild-type or mutant forms of EGFR. ABT-414 inhibits the growth of xenograft tumors with high EGFR expression and causes complete regressions and cures in the most sensitive models. Tumor growth inhibition is also observed in tumor models with EGFR mutations, including activating mutations and those with the exon 2-7 deletion [EGFR variant III (EGFRvIII)], commonly found in glioblastoma multiforme. ABT-414 exhibits potent cytotoxicity against glioblastoma multiforme patient-derived xenograft models expressing either wild-type EGFR or EGFRvIII, with sustained regressions and cures observed at clinically relevant doses. ABT-414 also combines with standard-of-care treatment of radiation and temozolomide, providing significant therapeutic benefit in a glioblastoma multiforme xenograft model. On the basis of these results, ABT-414 has advanced to phase I/II clinical trials, and objective responses have been observed in patients with both amplified wild-type and EGFRvIII-expressing tumors. Mol Cancer Ther; 15(4); 661-9. ©2016 AACR., (©2016 American Association for Cancer Research.)

Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indium-labeled version of ABT-806, [(111)In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIII-expressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity., (©2015 American Association for Cancer Research.)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents that improve glycemic control by inhibiting SGLT2-mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion (UGE) to <50% of maximal values because they do not inhibit SGLT1, which reabsorbs >50% of filtered glucose when SGLT2 is completely inhibited. This led us to test whether LP-925219, a small molecule dual SGLT1/SGLT2 inhibitor, increases UGE to maximal values in wild-type (WT) mice. We first tested LP-925219 inhibition of glucose transport by HEK293 cells expressing SGLT1 or SGLT2, and then characterized LP-925219 pharmacokinetics. We found that LP-925219 was a potent inhibitor of mouse SGLT1 (IC50 = 22.6 nmol/L) and SGLT2 (IC50 = 0.5 nmol/L), and that a 10 mg/kg oral dose was bioavailable (87%) with a long half-life (7 h). We next delivered LP-925219 by oral gavage to WT, SGLT1 knockout (KO), SGLT2 KO, and SGLT1/SGLT2 double KO (DKO) mice and measured their 24-h UGE. We found that, in vehicle-treated mice, DKO UGE was maximal and SGLT2 KO, SGLT1 KO, and WT UGEs were 30%, 2%, and 0.2% of maximal, respectively; we also found that LP-925219 dosed at 60 mg/kg twice daily increased UGE of SGLT1 KO, SGLT2 KO, and WT mice to DKO UGE levels. These findings show that orally available dual SGLT1/SGLT2 inhibitors can maximize 24-h UGE in mammals, and suggest that such agents merit further evaluation for their potential, in diabetic patients, to achieve better glycemic control than is achieved using selective SGLT2 inhibitors.

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and associated glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aqueous stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aqueous stable compounds, and addition of solubilizing groups resulted in a set of compounds with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clinical candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clinical trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure.

The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away from the highly conserved hinge region and instead resides in the hydrophobic pocket formed in the DFG-out conformation of the kinase, thus accounting for the high level of selectivity observed.

PNT100 is a 24-base, chemically unmodified DNA oligonucleotide sequence that is complementary to a region upstream of the BCL-2 gene. Exposure of tumor cells to PNT100 results in suppression of proliferation and cell death by a process called DNA interference. PNT2258 is PNT100 that is encapsulated in protective amphoteric liposomes developed to efficiently encapsulate the PNT100 oligonucleotide, provide enhanced serum stability, optimized pharmacokinetic properties and antitumor activity of the nanoparticle both in vivo and in vitro. PNT2258 demonstrates broad antitumor activity against BCL-2-driven WSU-DLCL2 lymphoma, highly resistant A375 melanoma, PC-3 prostate, and Daudi-Burkitt's lymphoma xenografts. The sequence specificity of PNT100 was demonstrated against three control sequences (scrambled, mismatched, and reverse complement) all encapsulated in a lipid formulation with identical particle characteristics, and control sequences did not demonstrate antiproliferative activity in vivo or in vitro. PNT2258 is currently undergoing clinical testing to evaluate safety and antitumor activity in patients with recurrent or refractory non-Hodgkin's lymphoma and additional studies are planned.

Background: Molecular testing of patients with advanced non-small cell lung cancer for personalized therapy often is limited by insufficient specimen from nonsurgical biopsies. We measured the feasibility, patient safety, and clinical impact of thoracic surgical tumor biopsy in patients with stage IV non-small cell lung cancer., Methods: This is a single institution retrospective analysis. Patients with stage IV non-small cell lung cancer undergoing elective surgical tissue biopsy for molecular analysis were evaluated from March 2011 to November 2012. Perioperative specific variables were measured., Results: Twenty-five patients with known or suspected stage IV non-small cell lung cancer undergoing surgical biopsy were identified. All cases were discussed at a multidisciplinary thoracic oncology conference or a multidisciplinary thoracic oncology clinic. Preoperative histologies included adenocarcinoma in 20 patients (80.0%) and squamous cell carcinoma in 2 patients (8.0%). Surgical procedures consisted of video-assisted thoracic surgery wedge biopsy (16, 64%), video-assisted thoracic surgery pleural biopsy (4, 16.0%), mediastinoscopy (2, 8.0%), supraclavicular/cervical lymph node excisional biopsy (3, 12.0%), and rib/chest wall resection (2, 8.0%). There were no deaths and 5 postoperative complications (20.0%). Surgery identified potentially targetable molecular information in 19 of the total patients undergoing operation (76.0%) and changed the treatment strategy in 14 patients (56.0%); 10 of the total cohort (40.0%) were enrolled into therapeutic targeted clinical trials., Conclusions: These data suggest that thoracic surgical biopsy can be safely performed in appropriately selected patients with stage IV non-small cell lung cancer and direct personalized therapy and enrollment into relevant clinical trials. Patients with advanced-stage non-small cell lung cancer should be discussed in a multidisciplinary setting to determine the need and strategy for thoracic surgical biopsy for molecular analysis., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo.

The first enantioselective organocatalytic Mukaiyama-Michael reaction using alpha,beta-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective addition of 2-silyloxy furans to unsaturated aldehydes to generate a variety of butenolide systems, an important chiral synthon found among many natural isolates. The (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted silyloxy furans to unsaturated aldehydes. A diverse range of aldehyde substrates can be accommodated in this new organocatalytic transformation. Application of this new asymmetric technology to the enantioselective total synthesis of spiculisporic acid and the corresponding 5-epi-spiculisporic acid analogue is also discussed.

Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental haploidy of chromosome 4p16.3. Its hallmark features include a 'Greek warrior helmet' facial appearance, mental retardation, various midline defects and seizures. The WHS critical region (WHSCR) lies between the Huntington's disease gene, HD, and FGFR3. In mice, the homologs of these genes map to chromosome 5 in a region of conserved synteny with human 4p16.3. To derive mouse models of WHS and map genes responsible for subphenotypes of the syndrome, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size. These mice represent the first animal models for WHS. This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissection of other deletion syndromes using the mouse.