DSM267

DSM267 is a triazolopyrimidine inhibitor of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), with an IC₅₀ of 38 nM, while its IC₅₀ against human DHODH exceeds 100000 nM. DSM267 is used for the in vitro systematic screening and characterization of the resistance evolution pathways of Plasmodium falciparum to DHODH inhibitors^[1][2]. In Vitro:DSM267 (72 h) induces Plasmodium falciparum 3D7 A10 parasites to develop resistance in vitro via single or combined point mutations in the DHODH gene or dhodh copy number increases, resulting in DSM267 EC₅₀ values ranging from 12.8 to >500 nM, representing 5.9- to >229-fold increases in resistance relative to wild-type parasites^[1].
DSM267 (72 h) induces pre-selected Plasmodium falciparum DHODH mutant lines to exhibit resistance, with DSM267 EC₅₀ values ranging from 31.5 to >200 nM, representing 9.1- to >57.8-fold increases in resistance relative to wild-type Dd2 or 3D7 parasites^[1].
DSM267 (72 h) induces Plasmodium falciparum 3D7⁰⁰⁸⁷/ᴺ⁹ parasites with the V532G DHODH mutation (selected with DSM265) to exhibit cross-resistance, with DSM267 EC₅₀ values ranging from 317 to 495 nM, representing 69.4- to 108.3-fold increases in resistance relative to wild-type 3D7⁰⁰⁸⁷/ᴺ⁹ parasites^[1].
DSM267 (72 h) induces Plasmodium falciparum 3D7 A10 and 3D7⁰⁰⁸⁷/ᴺ⁹ parasites with DHODH mutations (C276Y, L531F, G181C, F227Y) or dhodh copy number increases (selected with DSM265) to exhibit cross-resistance, with DSM267 EC₅₀ values ranging from 5.99 to 5361 nM, representing 1.3- to 2459-fold increases in resistance relative to wild-type parasites^[1].