DDD85646

DDD85646 is a potent inhibitor of Trypanosoma brucei N-myristoyltransferase (NMT), exhibiting half-maximal inhibitory concentration (IC₅₀) values of 2nM against T. brucei NMT (TbNMT) and 4nM against human NMT (hNMT)^[1]. DDD85646 effectively inhibits the proliferation of trypanosomes^[2], and also demonstrates antiviral activity by suppressing viral replication^[3-4].

In vitro, co-treatment of acute monocytic leukemia THP-1 cells with DDD85646 (10μM) and the ferroptosis inducer Erastin (10μM) for 36 hours enhanced susceptibility to ferroptosis—characterized by lipid peroxidation, glutathione depletion, and mitochondrial shrinkage—via inhibition of FSP1 localization to the cell membrane^[5]. Pretreatment of A549, HEK293T, HAP1, and Vero E6 cells with DDD85646 (0.1–10μM) for 1–5 hours, followed by infection with lymphocytic choriomeningitis virus (LCMV; MOI=0.05–1) for 24–72 hours, significantly suppressed viral protein expression, reduced viral titers, and decreased the number of infected cells^[6].

In vivo, oral administration of DDD85646 (12.5–50mg/kg) twice daily for 4 days to mice infected with Trypanosoma brucei strains S427 or STIB900 resulted in significant clearance of parasites from peripheral blood^[7]. Subcutaneous injection of DDD85646 (20–60mg/kg) once daily or every other day for 7–16 days in mice bearing DOHH2 or BL2 lymphoma xenografts led to significant suppression of tumor growth and induction of complete tumor regression^[8].

References:
[1] Spinks D, Smith V, Thompson S, et al. Development of Small-Molecule Trypanosoma brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode. ChemMedChem. 2015 Nov;10(11):1821-36.
[2] Begolo D, Erben E, Clayton C. Drug target identification using a trypanosome overexpression library. Antimicrob Agents Chemother. 2014 Oct;58(10):6260-4.
[3] Carnec X, Borges-Cardoso V, Reynard S, et al. Targeting n-myristoyltransferases promotes a pan-Mammarenavirus inhibition through the degradation of the Z matrix protein. PLoS Pathog. 2024 Dec 3;20(12):e1012715.
[4] Xiao P, Meng L, Cui X, et al. VP0 Myristoylation Is Essential for Senecavirus A Replication. Pathogens. 2024 Jul 21;13(7):601.
[5] Tan X, He Y, Yu P, et al. The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells. Mol Med. 2024 Jul 15;30(1):102.
[6] Witwit H, Betancourt CA, Cubitt B, et al. Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication. Viruses. 2024 Aug 26;16(9):1362.
[7] Brand S, Norcross NR, Thompson S, et al. Lead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis. J Med Chem. 2014 Dec 11;57(23):9855-69.
[8] Beauchamp E, Yap MC, Iyer A, et al. Targeting N-myristoylation for therapy of B-cell lymphomas. Nat Commun. 2020 Oct 22;11(1):5348.