McPherson, Kerry Silva; Zaino, Angela M.; Dash, Radha C.; Rizzo, Alessandro A.; Li, Yunfeng; Hao, Bing; Bezsonova, Irina; Hadden, M. Kyle; Korzhnev, Dmitry M. published an article in 2021. The article was titled 《Structure-Based Drug Design of Phenazopyridine Derivatives as Inhibitors of Rev1 Interactions in Translesion Synthesis》, and you may find the article in ChemMedChem.COA of Formula: C5H7N3 The information in the text is summarized as follows:
Rev1 is a protein scaffold of the translesion synthesis (TLS) pathway, which employs low-fidelity DNA polymerases for replication of damaged DNA. The TLS pathway helps cancers tolerate DNA damage induced by genotoxic chemotherapy, and increases mutagenesis in tumors, thus accelerating the onset of chemoresistance. TLS inhibitors have emerged as potential adjuvant drugs to enhance the efficacy of first-line chemotherapy, with the majority of reported inhibitors targeting protein-protein interactions (PPIs) of the Rev1 C-terminal domain (Rev1-CT). We previously identified phenazopyridine (PAP) as a scaffold to disrupt Rev1-CT PPIs with Rev1-interacting regions (RIRs) of TLS polymerases. To explore the structure-activity relationships for this scaffold, we developed a protocol for co-crystallization of compounds that target the RIR binding site on Rev1-CT with a triple Rev1-CT/Rev7R124A/Rev3-RBM1 complex, and solved an X-ray crystal structure of Rev1-CT bound to the most potent PAP analog. The structure revealed an unexpected binding pose of the compound and informed changes to the scaffold to improve its affinity for Rev1-CT. We synthesized eight addnl. PAP derivatives, with modifications to the scaffold driven by the structure, and evaluated their binding to Rev1-CT by microscale thermophoresis (MST). Several second-generation PAP derivatives showed an affinity for Rev1-CT that was improved by over an order of magnitude, thereby validating the structure-based assumptions that went into the compound design. The experimental process involved the reaction of 2,6-Diaminopyridine(cas: 141-86-6COA of Formula: C5H7N3)
2,6-Diaminopyridine(cas: 141-86-6) belongs to pyridine. Pyridine and its simple derivatives are stable and relatively unreactive liquids, with strong penetrating odours that are unpleasant.COA of Formula: C5H7N3