DTP3 is a selective GADD45β/MKK7 (growth arrest and DNA-damage-inducible β/mitogen-activated protein kinase kinase 7) inhibitor and is able to restore MKK7/JNK activation. DTP3 inhibits cancer-selective NF-κB survival pathway.
DTP3 physically interacts with MKK7, both in isolation and within the complex with GADD45β, and dissociates the GADD45β/MKK7 complex via an allosteric mechanism. DTP3 selectively kills cells and induces apoptosis in MM cells with functional MKK7 and elevated GADD45β expression without toxicity to normal cells. In addition, DTP3 displays synergistic activity with bortezomib in two different MM cell lines, exhibiting a combination index of 0.21 in U266 cells and of 0.56 in KMS-12 cells. [1]
DTP3 (14.5 mg/kg/day) exhibits potent antitumor activity against MM in mouse plasmacytoma model. [1]
[1] Tornatore L, et al. Cancer Cell. 2014, 26(4), 495-508. [2] Laura Tornatore, et al. Toxicol Rep . 2019 Apr 19;6:369-379.