biostudies-literatureKalebic DNIAID NIH HHSDefense Threat Reduction Agency/Fundamental Research to Counter Weapons of Mass Destruction, and the Department of Defense/Congressionally Directed Medical Research Programs1341https://www.ebi.ac.uk/biostudies/studies/S-EPMC12472322biostudies-literatureUnknown18(9)<b>Background/Objectives</b>: RMC-113, a 3-alkynyl-6-aryl-disubstituted isothiazolo[4,3-<i>b</i>]pyridine, is a dual inhibitor of the lipid kinases PIKfyve and PIP4K2C with broad-spectrum antiviral activity. The aim was to study the structure-activity relationship (SAR) of isothiazolo[4,3-<i>b</i>]pyridines as dual PIKfyve/PIP4K2C inhibitors. <b>Methods</b>: A series of isothiazolo[4,3-<i>b</i>]pyridines was synthesized by introducing structural variety at positions 3 and 6 of the central scaffold. The primary assay to guide the synthetic chemistry was a biochemical PIKfyve assay, with a number of analogues also tested for PIP4K2C binding affinity. Finally, isothiazolo[4,3-<i>b</i>]pyridines were also evaluated for antiviral and antitumoral activity in cell-based assays. <b>Results</b>: PIPharmaceuticals (Basel, Switzerland)Structure-Activity Relationship Study of 3-Alkynyl-6-aryl-isothiazolo[4,3-<i>b</i>]pyridines as Dual Inhibitors of the Lipid Kinases PIKfyve and PIP4K2C.PMC12472322R01 AI1585691R01AI158569-01 (awards HDTRA11810039 and W81XWH2210283 and W81XWH-16-1-0691)T32 AI007502Schols DEinav SSaul SRozenski JGao LJPersoons LTran DHNDehaen WMartinez-Gualda BKarim MKalebic DDe Jonghe SfalseStructure-Activity Relationship Study of 3-Alkynyl-6-aryl-isothiazolo[4,3-<i>b</i>]pyridines as Dual Inhibitors of the Lipid Kinases PIKfyve and PIP4K2C.<b>Background/Objectives</b>: RMC-113, a 3-alkynyl-6-aryl-disubstituted isothiazolo[4,3-<i>b</i>]pyridine, is a dual inhibitor of the lipid kinases PIKfyve and PIP4K2C with broad-spectrum antiviral activity. The aim was to study the structure-activity relationship (SAR) of isothiazolo[4,3-<i>b</i>]pyridines as dual PIKfyve/PIP4K2C inhibitors. <b>Methods</b>: A series of isothiazolo[4,3-<i>b</i>]pyridines was synthesized by introducing structural variety at positions 3 and 6 of the central scaffold. The primary assay to guide the synthetic chemistry was a biochemical PIKfyve assay, with a number of analogues also tested for PIP4K2C binding affinity. Finally, isothiazolo[4,3-<i>b</i>]pyridines were also evaluated for antiviral and antitumoral activity in cell-based assays. <b>Results</b>: PI2025-01-01T00:00:00Z2025 Sep2026-05-02T03:11:21.839Z2026-05-02T03:07:44.04ZS-EPMC124723224101121110.3390/ph18091341