Vertex Pharmaceuticals

About: Vertex Pharmaceuticals is a company organization based out in Boston, Massachusetts, United States. It is known for research contribution in the topics: Ivacaftor & Hepatitis C virus. The organization has 2135 authors who have published 2022 publications receiving 134750 citations. The organization is also known as: Vertex Pharmaceuticals Inc. & Vertex.

Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells

Abstract: The molecular mechanisms underpinning susceptibility loci for type 2 diabetes (T2D) remain poorly understood Coding variants in peptidylglycine α-amidating monooxygenase (PAM) are associated with both T2D risk and insulinogenic index Here, we demonstrate that the T2D risk alleles impact negatively on overall PAM activity via defects in expression and catalytic function PAM deficiency results in reduced insulin content and altered dynamics of insulin secretion in a human β-cell model and primary islets from cadaveric donors Thus, our results demonstrate a role for PAM in β-cell function, and establish molecular mechanisms for T2D risk alleles at this locus Coding variants in peptidylglycine α-amidating monooxygenase (PAM) associated with type 2 diabetes risk negatively impact overall PAM activity via defects in expression and catalytic function, resulting in reduced insulin content and altered dynamics of insulin secretion

Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ.

Abstract: Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.

A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

Abstract: New drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drug-resistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates of Mycobacterium tuberculosis in vitro (MICs of 0.03 to 0.30 μg/ml and 0.08 to 5.48 μg/ml, respectively) and reduces mycobacterial burdens in lungs of infected mice in vivo . VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormant M. tuberculosis bacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains of Mycobacterium abscessus, Mycobacterium avium complex, and Mycobacterium kansasii (MICs of 0.1 to 2.0 μg/ml), as well as that of several strains of Nocardia spp. (MICs of 0.1 to 1.0 μg/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing of M. tuberculosis than did VXc-486 in vivo . In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilized M. tuberculosis infection when combined with rifapentine-pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections.

Orchestrated triple C-H activation reactions using two directing groups: rapid assembly of complex pyrazoles.

Abstract: A sequential triple C-H activation reaction directed by a pyrazole and an amide group leads to the well-controlled construction of sterically congested dihydrobenzo[e]indazole derivatives. This cascade reaction demonstrates that the often problematic competing C-H activation pathways in the presence of multiple directing groups can be harvested by design to improve step economy in synthesis. Pyrazole as a relatively weak coordinating group is shown to direct Csp3-H activation for the first time.