Identification of Novel Dual-Target Estrogen Receptor α Degraders with Tubulin Inhibitory Activity for the Treatment of Endocrine-Resistant Breast Cancer.

Endocrine resistance remains a significant problem in the clinical treatment of estrogen receptor α-positive (ERα) breast cancer (BC). In this study, we developed a series of novel dual-functional ERα degraders based on a bridged bicyclic scaffold with selenocyano (SeCN) side chains. These compounds displayed potent ERα degradation and tubulin depolymerization activity.

CDK12 and Integrator-PP2A complex modulates LEO1 phosphorylation for processive transcription elongation.

Cyclin-dependent kinase 12 (CDK12) interacts with cyclin K to form a functional nuclear kinase that promotes processive transcription elongation through phosphorylation of the C-terminal domain of RNA polymerase II (Pol II). To gain a comprehensive understanding of CDK12's cellular function, we used chemical genetic and phosphoproteomic screening to identify a landscape of nuclear human CDK12 substrates, including regulators of transcription, chromatin organization, and RNA splicing. We further validated LEO1, a subunit of the polymerase-associated factor 1 complex (PAF1C), as a bona fide cellular substrate of CDK12.

Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer and .

The estrogen receptor (ER) is a well-established target for endocrine therapies of ER-positive breast cancer (ER BC), but endocrine resistance limits the efficacy of clinical drugs. Using proteolysis targeting chimera (PROTAC) technology to degrade ERα may be an effective alternative to endocrine therapies. Herein, we disclose a novel series of potent and selective ERα PROTACs based on an oxabicycloheptane sulfonamide (OBHSA) scaffold, with no associated ERβ degradation.

OBHS Drives Abnormal Glycometabolis Reprogramming via GLUT1 in Breast Cancer.

Due to the poor metabolic conditions fomenting the emergence of the Warburg effect (WE) phenotype, abnormal glycometabolism has become a unique and fundamental research topic in the field of tumor biology. Moreover, hyperglycemia and hyperinsulinism are associated with poor outcomes in patients with breast cancer. However, there are a few studies on anticancer drugs targeting glycometabolism in breast cancer.

Discovery of Novel Bicyclic Phenylselenyl-Containing Hybrids: An Orally Bioavailable, Potential, and Multiacting Class of Estrogen Receptor Modulators against Endocrine-Resistant Breast Cancer.

Breast cancer (BC) is a multifactorial disease and is prone to drug resistance during treatment. In this study, we described a new class of multifunctional estrogen receptor (ER) modulators ground on a prerogative indirect antagonism skeleton (OBHS, oxabicycloheptene sulfonate) of ER containing a phenylselenyl group. Compound showed significant antiproliferative activities against tamoxifen-sensitive (MCF-7) and -resistant (LCC2) cells.

Ligand-induced native G-quadruplex stabilization impairs transcription initiation.

G-quadruplexes (G4s) are noncanonical DNA secondary structures formed through the self-association of guanines, and G4s are distributed widely across the genome. G4 participates in multiple biological processes including gene transcription, and G4-targeted ligands serve as potential therapeutic agents for DNA-targeted therapies. However, genome-wide studies of the exact roles of G4s in transcriptional regulation are still lacking.

Genomic profiling of native R loops with a DNA-RNA hybrid recognition sensor.

An R loop is a unique triple-stranded structure that participates in multiple key biological processes and is relevant to human diseases. Accurate and comprehensive R loop profiling is a prerequisite for R loops studies. However, current R loop mapping methods generate large discrepancies, therefore an independent method is in urgent need.

Quantifying Induced Polarization of Conductive Inclusions in Porous Media and Implications for Geophysical Measurements.

Induced polarization (IP) mapping has gained increasing attention in the past decades, as electrical induced polarization has been shown to provide interesting signatures for detecting the presence of geological materials such as clay, ore, pyrite, and potentially, hydrocarbons. However, efforts to relate complex conductivities associated with IP to intrinsic physical properties of the corresponding materials have been largely empirical. Here we present a quantitative interpretation of induced polarization signatures from brine-filled rock formations with conductive inclusions and show that new opportunities in geophysical exploration and characterization could arise.

Modeling Oil Recovery for Mixed Macro- and Micro-Pore Carbonate Grainstones.

In general, modeling oil-recovery is a challenging problem involving detailed fluid flow calculations with required structural details that challenge current experimental resolution. Recent laboratory experiments on mixed micro- and macro-pore suggest that there is a systematic relationship between remaining oil saturation (ROS) and the fraction of micro-pores. Working with experimental measurements of the pores obtained from X-ray tomography and mercury intrusion capillary pressure porosimetry, we define a digital rock model exemplifying the key structural elements of these carbonate grainstones.

Intrinsic electron-phonon resistivity of Bi2Se3 in the topological regime.

We measure the temperature-dependent carrier density and resistivity of the topological surface state of thin exfoliated Bi(2)Se(3) in the absence of bulk conduction. When the gate-tuned chemical potential is near or below the Dirac point, the carrier density is strongly temperature-dependent, reflecting thermal activation from the nearby bulk valence band, while, above the Dirac point, unipolar n-type surface conduction is observed with negligible thermal activation of bulk carriers. In this regime, linear resistivity vs temperature reflects intrinsic electron-acoustic phonon scattering.

Theory of 2D transport in graphene for correlated disorder.

We theoretically revisit graphene transport properties as a function of carrier density, taking into account possible correlations in the spatial distribution of the Coulomb impurity disorder in the environment. We find that the charged impurity correlations give rise to a density-dependent graphene conductivity, which agrees well qualitatively with the existing experimental data. We also find, quite unexpectedly, that the conductivity could increase with increasing impurity density if there is sufficient interimpurity correlation present in the system.