DTP3 TFA

DTP3 is an inhibitor of GADD45β/MKK7 complex [1].

GADD45β is an antiapoptotic factor regulated by NF-kB. MAP kinase kinase 7 (MKK7) is a JNK kinase. GADD45β/MKK7 complex is the downstream module of NF-κB and becomes a therapeutic target in multiple myeloma (MM) [1].

DTP3 is an inhibitor of GADD45β/MKK7 complex. DTP3 interacted with and caused a significant conformational change of GADD45β/MKK7 complex in a dose dependent way, as well as of the isolated MKK7 protein. DTP3 bound to MKK7 with KD value of 64.81 nM. By binding to MKK7, DTP3 dissociated the GADD45b/MKK7 complex through an allosteric mechanism and caused conformational rearrangement of the kinase. In both MM and non-MM cell lines with high expression of GADD45B, DTP3 inhibited cell growth and displayed potent and selective activity and was completely inactive in tumor cell lines with low GADD45B expression. Also, DTP3 effectively activated tumor necrosis factor α (TNFα, a potent inducer of JNK) and JNK [1].

In mice bearing myeloma xenografts, DTP3 (14.5 mg/kg/day) significantly inhibited tumor growth through induction of JNK activation and apoptosis [1].

Reference:
[1].  Tornatore L, Sandomenico A, Raimondo D, et al. Cancer-Selective Targeting of the NF-kB
Survival Pathway with GADD45b/MKK7 Inhibitors.  Cancer Cell, 2014, 26(4): 495-508.