2 research outputs found
Nicotinamide Phosphoribosyltransferase Inhibitor as a Novel Payload for Antibody–Drug Conjugates
Antibody–drug
conjugates (ADCs) are a novel modality that
allows targeted delivery of potent therapeutic agents to the desired
site. Herein we report our discovery of NAMPT inhibitors as a novel
nonantimitotic payload for ADCs. The resulting anti-c-Kit conjugates
(<b>ADC-3</b> and <b>ADC-4</b>) demonstrated <i>in
vivo</i> efficacy in the c-Kit positive gastrointestinal stromal
tumor GIST-T1 xenograft model in a target-dependent manner
6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors
Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism