Rapid Evolution of a Fragment-like Molecule to Pan-Metallo-Beta-Lactamase Inhibitors: Initial Leads toward Clinical Candidates.

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by , discovered earlier as metallo-beta-lactamase inhibitors, was selected for virtual screening.

Design and manufacture of an all-polymeric integrated multimode interferometer for visible photonics.

This work demonstrates an integrated multimode interferometer (MMI) based on a fully polymeric platform and optimized for visible range operation. The dimensions of a 2×2 MMI are first calculated analytically and simulated using finite elements method. The devices are manufactured using two layers of negative tone photoresists.

Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer.

Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed and synthesized to access a previously unexplored chemical space. The assessment of biochemical affinity and cellular potency, along with computational, structural, and biophysical characterization, was applied to influence the design and optimization of novel STING agonists, resulting in the discovery of MK-1454 as a molecule with appropriate properties for clinical development. When administered intratumorally to immune-competent mice-bearing syngeneic tumors, MK-1454 exhibited robust tumor cytokine upregulation and effective antitumor activity.

Publisher Correction: A mass spectrometry-based proteome map of drug action in lung cancer cell lines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.