August 25th Characterizing and understanding the formation of cysteine conjugates and other by-products in a random, lysine-linked antibody drug conjugate https://www.tandfonline.com/doi/full/10.1080/19420862.2021.1974150#abstract Abstract This study describes the characterization of conjugation sites for a random, lysine conjugated 2-iminothiolane (2-IT) based antibody-drug-conjugate synthesized from an IgG1 antibody and a duocarmycin analog-based payload-linker. Of the 80 putative lysine sites, 78 were found to be conjugated via tryptic peptide mapping and LC-HRMS. Surprisingly, seven cysteine-linked conjugated peptides were also detected…

Oldest Pharmacy Florence is world-renowned for its rich cultural heritage, home to Renaissance art, grand architecture, and literary giants like Dante Alighieri. Yet, tucked away in this treasure-filled city lies a lesser-known marvel: the oldest functioning pharmacy in the world. The Santa Maria Novella Pharmacy was founded in 1221 by a Dominican monk who began cultivating herbs to create medicinal balms, tinctures, and perfumes for their monastery and local patients. Officially opened to the public…

July 28th Real Way to Target Gram-Negative Pathogens: Discovery of a Novel Helicobacter pylori Antibiotic Class https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5c00112 Abstract In an era of escalating antibiotic resistance, there is a pressing need for innovative strategies to develop novel antibiotics. Gram-negative bacteria, characterized by their robust dual-membrane, are intrinsically resistant to a wide range of antibiotics and can readily develop new resistances. Members of this bacterial class comprise numerous pathogenic organisms, including the primary cause of gastric cancer, Helicobacter pylori. In…

June 30th Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.4c02314 Abstract Oncogenic RAS mutations are among the most common in human cancers. To target the active, GTP-bound state of RAS(ON) directly, we employed an innovative tri-complex inhibitor (TCI) modality. Formation of a complex with an intracellular chaperone protein CypA, an inhibitor, and a target protein RAS blocks effector binding,…

May 26th Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.4c02751 Abstract N-Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical properties…