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A boundary helical Luttinger liquid (HLL) with broken bulk time-reversal symmetry belongs to a unique topological class that may occur in antiferromagnets (AFM). Here, we search for signatures of HLL on the edge of a recently discovered topological AFM, MnBi

PDF file 58K, Supplementary Figure S5: Basal AKT phosphorylation is higher in SCLC lines with either PIK3CA mutation or PTEN loss

PDF file 104K, Legend

Supplementary Table SI XLS file 19K, Supplementary Table SI: Kinase selectivity of PF-4989216

Purpose: Constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors via either gene mutation in the p110α catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer (SCLC) have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation.Experimental Design: A panel of SCLC cell lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays, including PI3K pathway signaling, cell viability, apoptosis, cell-cycle progression, and cell transformation. SCLC cell lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition (TGI) by PF-4989216 treatment.Results: PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator (BIM)-mediated apoptosis nor was there any effect on cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss.Conclusions: Our results suggest that PF-4989216 is a potential cancer drug candidate for patients with SCLC with PIK3CA mutation but not PTEN loss. Clin Cancer Res; 20(3); 631–43. ©2013 AACR.

Helical Luttinger liquid (HLL) is a class of one-dimensional liquids with locked electron spin orientation and momentum. Boundary of a quantum spin Hall insulator is a good example of time-reversal symmetry (TRS) protected HLL, but its topological protection is compromised under finite magnetic field. Boundary HLL with broken bulk TRS belongs to a different topological class which may occur in antiferromagnets. The recently discovered van der Waals antiferromagnet (AFM) MnBi2Te4 offers rich topological band structures which critically relies on the magnetic structure and layer number. Here, we search for signatures of HLL on the edge of even-layer MnBi2Te4 thin flakes by combining magneto-transport and scanning superconducting quantum interference device microscopy. We directly image helical edge current in the AFM ground state appearing when the chemical potential was gated to the charge neutral point. Such helical edge state accompanies an insulating bulk which is topologically distinct from the ferromagnetic Chern insulator phase as revealed in a magnetic field driven quantum phase transition of the bulk. The edge conductance of the AFM order follows a power-law as a function of temperature and source-drain bias which serves as strong evidence for HLL. Such HLL scaling is robust at finite fields below the quantum critical point. The observed HLL in a layered AFM semiconductor represents a highly tunable topological matter compatible with future spintronics and quantum computation.

Monolayers of a prototypical cuprate high transition-temperature (TC) superconductor Bi2Sr2CaCu2O8+δ (Bi2212) was recently found to show TC and other electronic properties similar to those of the bulk. The robustness of superconductivity in an ideal two-dimensional (2D) system was an intriguing fact that defied the Mermin-Wagner theorem. Here, we took advantage of the high sensitivity of scanning SQUID susceptometry to image the phase stiffness throughout the phase transition of Bi2212 in the 2D limit. We found susceptibility oscillated with flux between diamagnetism and paramagnetism in a Fraunhofer-like pattern up till TC. The temperature and sample size-dependence of the modulation period agreed well with our Coulomb gas analogy of a finite 2D system based on Berezinskii–Kosterlitz–Thouless (BKT) transition. In the multilayers, the susceptibility oscillation differed in a small temperature regime below TC in consistent with a dimensional-crossover led by interlayer coupling. Serving as strong evidence of BKT transition in the bulk, there appeared a sharp superfluid density jump at zero-field and paramagnetism at small fields just below TC. These results unified the phase transitions from the monolayer Bi2212 to the bulk as BKT transition with finite interlayer coupling. This elucidating picture favored the pre-formed pairs scenario for the underdoped cuprates regardless of lattice dimensionality.

Quantitative characterization of pore structure in shale can provide basic parameters for evaluation of the shale-gas reservoir quality. However, it is difficult to use conventional methods to accurately and comprehensively characterize the pore structure parameters. We take shale samples from the Longmaxi Formation in the Sichuan Basin as the study object, and we use the high-pressure mercury intrusion, nitrogen adsorption, and carbon dioxide adsorption methods to characterize the whole aperture distribution. We found that the pore size in shale is positively related to the transverse relaxation time ([Formula: see text] value) and there exists a conversion coefficient. We have developed a new method combining nuclear magnetic resonance (NMR) with hybrid detection methods for testing the pore size distribution, and we optimized the conversion coefficient between pore size obtained by a hybrid detection method and the [Formula: see text] value. NMR can then characterize the pore size distribution by conversion coefficient. This method can effectively make up for the deficiency of conventional methods for pore size distribution characterization by a single method. Our results indicate that the macropore, mesopore, and micropore in shale are very developed, and the pore shapes are ink bottle and slit-like. Shale pores mainly consist of mesopore and micropore, contributing to approximately 74.33% of pore volume, whereas micropore contributes approximately 70.18% of specific surface area (SSA). Therefore, the macropore has a limited effect on the pore volume and SSA. In addition, the establishment of whole aperture distribution characterization by the new method can more comprehensively reflect the actual pore distribution in shale.

This study incorporates X-ray computed tomography (CT) technology into the in-situ observation of the xenon hydrate formation process in sand sediments under excess gas conditions. While the scanning images were used to obtain microscopic distribution information of the hydrate, we implemented the finite element method (FEM) to calculate the resistivity of the hydrate-bearing samples obtained from scanning images. Consequently, it was observed that the resistivity index (RI) versus hydrate saturation (Sh) data matched better with our new calculation model rather than the simple Archie formula fitting model (i.e. experimental fitting model). Besides, we calculated the resistivity versus the hydrate saturation curves based on digital rock models with idealized hydrate distributions. These distributions included adhesive type, cemented type and scattered type. Observation of microscopic distribution and simulation results indicated that the resistivity versus hydrate saturation exhibited certain differences for the three types of hydrate distributions. We also found that saturation exponent (n) is a function of the hydrate saturation (Sh), which can be applied in the proposed new calculation model in order to calculate the resistivity versus hydrate saturation data. This suggests that the established model is a useful methodology for the purpose of saturation calculations and reservoir identification in hydrate-bearing sediments.

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-pr...

Rh-catalyzed C–H functionalization of O-pivaloyl benzhydroxamic acids with propene gas provides access to 4-methyl-substituted dihydroisoquinolones. Good to excellent levels of regioselectivity are...

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C–C and C–N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents.

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.

On the basis of a more practical and scalable route to an iodothiophene, an efficient and reliable synthesis has been developed for three selective PI3K inhibitors. From this advanced intermediate, the three title compounds were each prepared in five additional steps. Key learnings also include: high throughput experimentation (HTE) screening toward a more robust Suzuki coupling, a more efficient triazole synthesis, and an acid/base cleanup developed to purify the final compounds. The final enabled synthesis required no column chromatography.

Opening one ring to tack on another Curious chemists have long sought to learn just how tightly carbon atoms can be bound together. For instance, it's possible to form a bond between two opposite corners of an already strained four-membered ring to make an edge-sharing pair of triangles. Gianatassio et al. have now devised a general use for these and related molecular curiosities. They show that appropriately modified nitrogen centers can pop open the most highly strained bond, leaving the more modestly strained ring motif intact. In this way, small rings can emerge as a convenient diversifying element in compounds, including new pharmaceutical candidates. Science , this issue p. 241

The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.

Purpose: Constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors via either gene mutation in the p110α catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer (SCLC) have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation. Experimental Design: A panel of SCLC cell lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays, including PI3K pathway signaling, cell viability, apoptosis, cell-cycle progression, and cell transformation. SCLC cell lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition (TGI) by PF-4989216 treatment. Results: PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator (BIM)-mediated apoptosis nor was there any effect on cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss. Conclusions: Our results suggest that PF-4989216 is a potential cancer drug candidate for patients with SCLC with PIK3CA mutation but not PTEN loss. Clin Cancer Res; 20(3); 631–43. ©2013 AACR.

Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.

The cocrystal structure of a library hit was used to design a novel series of CHK1 inhibitors. The new series retained the critical hydrogen-bonding groups of the resorcinol moiety for binding but lacked the phenolic anilide moiety. The newly designed compounds exhibited similar enzymatic activity, while demonstrating increased cellular potency. Compound 10c, showing no single agent effect, potentiated the antiproliferative effect of Gemcitabine in both prostate and breast cancer cell lines.

Aberrant PI3K/AKT signaling occurs commonly in cancer. Gene mutation, amplification, and copy number gains in the catalytic p110α of PI3K have been shown in a variety of human cancers. Tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates the 3-phosphoinositides and is frequently mutated, deleted, or down-regulated in many human cancers to constitutively activate the PI3K pathway. Small cell lung cancer (SCLC) patients have poor prognosis; response to second-line chemotherapy for patients with refractory disease is less than 10%, and survival is 3-4 months. Multiple phase III trials have been conducted, however the survival of SCLC patients has not significantly improved over the years. In this study, we characterized a selective PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway may be a potential therapy for SCLC. PF-4989216 inhibits phosphorylation of PI3K downstream molecules and subsequently leads to induction in apoptosis and cell cycle block, as well as inhibition of cell proliferation, transformation, and xenograft tumor growth in SCLCs harboring a PIK3CA mutation. Moreover, our results suggest that there may be different mechanisms of tumorigenesis between PIK3CA mutation and PTEN loss in SCLCs, and indicate that PF-4989216 is a potential cancer drug candidate for small-cell lung cancer patients harboring a PIK3CA mutation. Citation Format: Marlena Walls, Sangita M. Baxi, Pramod P. Mehta, Elizabeth Epps, Heather Estrella, Kevin KC Liu, JinJiang Zhu, Chunze Li, Tod Smeal, Min-Jean Yin. Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor, PF-4989216. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3257. doi:10.1158/1538-7445.AM2013-3257

The title compound, C9H10N2O2S, was obtained from the treatment of ethyl 4-cyano-3-hydroxy-5-morpholinothiophene-2-carboxylate with concentrated HCl. The mean plane of the essentially planar dihydrothiophene ring is almost orthogonal to the mirror plane of the N-morpholine substituent, making a dihedral angle of 87.2 (2)°.