The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico‐chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE‐987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader‐antibody conjugate by attaching GNE‐987 to an anti‐CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen‐specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.

Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC = 0.94 nM, BRET IC = 6.2 nM; BRD4(1) IC = 5100 nΜ) that maintained good in vivo PK properties in multiple species. Compound 19 displays antitumor activity in an AML tumor model and was also shown to decrease Foxp3 transcript levels in a dose dependent manner.

The FDA recommends rosuvastatin dosage reductions in Asian patients because pharmacokinetic studies have demonstrated an approximate two-fold increase in median exposure to rosuvastatin in Asian subjects when compared to Caucasian controls. Yet, no explanation for this ethnic difference has been confirmed. Here we show that rosuvastatin exposure in Asians and Whites does not differ significantly when all subjects are wildtype carriers for both Solute Carrier Organic anion transporter1B1 *1a and ATP Binding Cassette Subfamily G Member 2 c.421 transporters in a two arm, randomized, cross-over rosuvastatin pharmacokinetics study in healthy White and Asian volunteers. For single rosuvastatin doses, AUC0–48 were 92.5(±36.2) and 83.5(±32.2) ng/mL*hr and Cmax were 10.0(±4.1) and 7.6(±3.0) ng/mL for Asians and Whites, respectively. When transporters were inhibited by intravenous rifampin, rosuvastatin AUC0–48 and Cmax also showed no ethnic differences. Our study suggests that both SLCO1B1 and ABCG2 polymorphisms are better predictors of rosuvastatin exposure than ethnicity alone and could be considered in precision medicine dosing of rosuvastatin.

No abstract

The enhanced sensitivity for detection of biomarkers based on CdTe quantum dot functionalized silica nanosphere labels can be achieved by an increase in CdTe QD loading per sandwiched immunoreaction.

No abstract

No abstract

Layered graphitic carbon nitride (g-C3N4) is a typical polymeric semiconductor with an sp 2 π-conjugated system having great potential in energy conversion, environmental purification, materials science, etc., owing to its unique physicochemical and electrical properties. However, bulk g-C3N4 obtained by calcination suffers from a low specific surface area, rapid charge carrier recombination, and poor dispersion in aqueous solutions, which limit its practical applications. Controlling the size of g-C3N4 (e.g., preparing g-C3N4 nanosheets) can effectively solve the above problems. Compared with the bulk material, g-C3N4 nanosheets have a larger specific surface area, richer active sites, and a larger band gap due to the quantum confinement effect. As g-C3N4 has a layered structure with strong in-plane C-N covalent bonds and weak van der Waals forces between the layers, g-C3N4 nanosheets can be prepared by exfoliating bulk g-C3N4. Alternatively, g-C3N4 nanosheets can otherwise be obtained through the anisotropic assembly of organic precursors. Nevertheless, some of these methods have various limitations, such as high energy consumption, are time consuming, and have low yield. Accordingly, developing green and cost-effective exfoliation and preparation strategies for g-C3N4 nanosheets is necessary. Herein, the research progress of the exfoliation and preparation strategies (including the thermal oxidation etching process, the ultrasound-assisted route, the chemical exfoliation, the mechanical method, and the template method) for two-dimensional C3N4 nanosheets are introduced. Their features are systematically analyzed and the perspectives and challenges in the preparation of g-C3N4 nanosheets are discussed. This study emphasizes the following: (1) The preparation method of g-C3N4 nanosheets should be properly selected according to the practical application needs. Additionally, various strategies (such as chemical method and ultrasonic method) can be combined to exfoliate nanosheets from bulk g-C3N4;(2) More reasonable nano-or even subnanostructured g-C3N4 nanosheets should be continuously explored; (3) Novel modification strategies, such as defective engineering, heterojunction construction, and surface functional group regulation, should be introduced to improve the reactivity and selectivity of the g-C3N4 nanosheets; (4) The application of in situ characterization techniques (such as in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), electron spin resonance (ESR) spectroscopy, and Raman spectroscopy) should also be strengthened to monitor the detailed catalytic process and investigate the g-C3N4 nanosheet structure-efficiency relationship. (5) To gain a deeper understanding of the relationship between the macroscopic properties and the microscopic structure, the combination of theoretical calculations and experimental results should be strengthened, which will be beneficial for exploiting high-quality g-C3N4 nanosheets.