Selection of oral bioavailability enhancing formulations during drug discovery.

The objective of this paper was to identify oral bioavailability enhancing approaches for a poorly water-soluble research compound during drug discovery stages using minimal amounts of material. LCQ789 is a pBCS (preclinical BCS) Class II compound with extremely low aqueous solubility (<1 µg/mL) and high permeability, therefore, resulting in very low oral bioavailability in preclinical species (rats and dogs). A number of solubility and/or dissolution enhancing approaches including particle size reduction, solid dispersions, lipid-based formulations and co-crystals, were considered in order to improve the compound's oral bioavailability. High-Throughput Screening (HTS) and in silico modeling (GastroPlus™) were utilized to minimize the compound consumption in early discovery stages. In vivo evaluation of selected physical form and formulation strategies was performed in rats and dogs. Amongst the formulation strategies, optimized solid dispersion and lipid-based formulation provided significant improvement in drug dissolution rate and hence, oral bioavailability. In addition, a significant impact of physical form on oral bioavailability of LCQ789 was observed. In conclusion, a thorough understanding of not only the formulation technique but also the physical form of research compounds is critical to ensure physical stability, successful pharmacokinetic (PK) profiling and early developability risk assessment.

Author Correction: Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc. Chicago, IL, USA was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features.

Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 - tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation-indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.

NaV3 (OH)6 (SO4 )2 : A Kagomé-Type Vanadium(III) Compound with Strong Intralayer Ferromagnetic Interactions.

A dominant ferromagnetic exchange interaction propagates about the magnetic sites of the Kagomé lattice of the title compound through the bridging hydroxy groups (see section of the structure). This is at variance with the antiferromagnetic exchange observed for jarosite and its derivatives. The ferromagnetism probably arises from the d2 electron count of the VIII centers.

Magnetic properties of a homologous series of vanadium jarosite compounds.

Redox-based, hydrothermal synthetic methodologies have enabled the preparation of a new series of stoichiometrically pure jarosites of the formula, AV(3)(OH)(6)(SO(4))(2) with A = Na(+), K(+), Rb(+), Tl(+), and NH(4)(+). These jarosites represent the first instance of strong ferromagnetism within a Kagomé layered framework. The exchange interaction, which is invariant to the nature of the A(+) ion (theta(CW) approximately equal to +53(1) K), propagates along the d(2) magnetic sites of the triangular Kagomé lattice through bridging hydroxyl groups. An analysis of the frontier orbitals suggests this superexchange pathway to possess significant pi-orbital character. Measurements on a diamagnetic host jarosite doped with magnetically dilute spin carriers, KGa(2.96)V(0.04)(OH)(6)(SO(4))(2), reveal significant single-ion anisotropy for V(3+) ion residing in the tetragonal crystal field. This anisotropy confines the exchange-coupled moments to lie within the Kagomé layer. Coupling strengths are sufficiently strong to prevent saturation of the magnetization when an external field is applied orthogonal to the Kagomé layer. Antiferromagnetic ordering of neighboring ferromagnetic Kagomé layers becomes dominant at low temperatures, characteristic of metamagnetic behavior for the AV(3)(OH)(6)(SO(4))(2) jarosites. This interlayer exchange coupling decreases monotonically with increasing layer spacing along the series, A = Na(+), K(+), Rb(+), NH(4)(+), and Tl(+), and it may be overcome by the application of external field strengths in excess of approximately 6 kOe.

Spin frustration in 2D kagomé lattices: a problem for inorganic synthetic chemistry.

A kagomé antiferromagnet presents an ideal construct for studying the unusual physics that result from the placement of magnetically frustrated spins on a low-dimensional lattice. Jarosites are the prototype for a spin-frustrated magnetic structure, because these materials are composed exclusively of kagomé layers. Notwithstanding, jarosite-type materials have escaped precise magnetic characterization over the past three decades, because they are notoriously difficult to prepare in pure and single-crystal forms. These hurdles have been overcome with the development of redox-based hydrothermal methods. Armed with pure and crystalline materials, several perplexing issues surrounding the magnetic properties of the jarosites have been resolved, yielding a detailed and comprehensive picture of the ground-state physics of this kagomé lattice.

Structural and magnetic properties of vanadyl dichloride solvates: from molecular units to extended hydrogen-bonded solids.

The preparation, structural characterization and magnetic properties of three solvent adducts of VOCl(2), trans-VOCl(2)(THF)(2)(H(2)O) (1), trans-VOCl(2)(H(2)O)(2).2Et(2)O (2) and cis-VOCl(2)(MeOH)(3) (3) are described. In these solids, hydrogen bonding among the inorganic complexes is the critical determinant of the formation of extended magnetic networks. Compound forms one-dimensional double chains where alternating monomers from the two branches of the chain are hydrogen bonded via the V-Cl ... H-O-V network (with an axial water molecule and equatorial chloride ions). Magnetic studies indicate no interaction among the vanadyl centers. The paramagnetism of 1 is consistent with the extension of the network from the hydrogen donor site of the axial water, which is orthogonal to the d(xy) magnetic orbital. Compound 2 forms one-dimensional chains with water molecules of adjacent monomers held together by hydrogen bonds to ether molecules (V-O-H ... O(ether) ... H -O-V). The chain network radiates only through the equatorial plane of the complex where the water molecules are located. The presence of the intervening solvent molecule between hydrogen bonds of the primary coordination sphere magnetically insulates metal centers and compound is also a simple paramagnet. Removal of the solvent turns on the magnetic interaction and neighboring spin centers couple antiferromagnetically. Compound 3 forms a layered structure via V-Cl ... H-O-V hydrogen bonding, where all the hydrogen donor sites participate in the formation of the network. The vanadyl spin centers, at distances of 5.5 and 6.5 A from each other, couple antiferromagnetically (J/k=-0.7 K). Thus, magnetic coupling among metal centers is achieved when the hydrogen bond network directly radiates from the coordination plane containing the magnetic orbital. These results further support the utility of hydrogen bond as a viable design element in the construction of low dimensional, magnetic solids.