MRx102, a triptolide derivative, has potent antileukemic activity in vitro and in a murine model of AML

Abstract

Triptolide, isolated from the herb Tripterygium wilfordii, has been shown to potently induce apoptosis in various malignant cells by inhibiting RNA synthesis and NF-κB activity. Previously, we showed that triptolide promotes apoptosis in acute myeloid leukemia (AML) cells via the mitochondria-mediated pathway, in part by decreasing levels of the anti-apoptotic proteins XIAP and Mcl-1. MRx102 is a triptolide derivative currently in preclinical development. Here, we show that MRx102 potently promoted apoptosis in AML cell lines, with EC50 values of 14.5 ± 0.6 nM and 37.0 ± 0.9 nM at 48 hours for OCI-AML3 and MV4-11 cells, respectively. MRx102, at low nanomolar concentrations, also induced apoptosis in bulk, CD34+ progenitor, and more importantly CD34+CD38− stem/progenitor cells from AML patients, even when they were protected by co-culture with bone marrow mesenchymal stromal cells. MRx102 decreased XIAP and Mcl-1 protein levels and inhibited RNA synthesis in OCI-AML3 cells. In vivo, MRx102 greatly decreased leukemia burden and increased survival time in NOD/SCID mice harboring Ba/F3-ITD cells. Collectively, we demonstrated that MRx102 has potent antileukemic activity both in vitro and in vivo, has the potential to eliminate AML stem/progenitor cells and overcome microenvironmental protection of leukemic cells, and warrants clinical investigation.

Preclinical antileukemic activity, toxicology, toxicokinetics and formulation development of triptolide derivative MRx102

“…The concentration curves for MRx102 and triptolide shown in Fig. 1 are offset with lower triptolide concentrations being effective, as anticipated [17, unpublished results]. A comparison of the MRx102 and triptolide results (Table 2) indicates that MRx102 is less potent than triptolide.…”

“…We reported previously that MRx102 induces apoptosis in leukemic cells including leukemic stem/progenitor cells from AML patients [17]. We compared the in vitro anti-leukemia activity of MRx102 to triptolide in samples from AML patients.…”

“…The decrease in the major component of RNA POL II is closely correlated with the cytotoxic activity of triptolide [24]. Triptolide decreases mRNA and protein levels of XIAP and Mcl-1 in myeloid leukemia cells [3], and we showed that MRx102 also decreased XIAP and Mcl-1 protein levels and inhibited RNA synthesis in leukemia cells [17]. …”

“…The F60008 prodrug requires conversion by serum esterases to express in vitro activity, whereas MRx102 does not require exposure to serum for in vitro efficacy (Table 1) [17]. There is a similar requirement for the triptolide prodrug Minnelide that is inactive without conversion by alkaline phosphatase [19].…”

“…This is a goal similar to F60008, which displayed inconsistent conversion, widely divergent triptolide blood levels and a dangerously high triptolide C max in some patients [5, 6]. Unlike MRx102, F60008 requires conversion by serum esterases to express in vitro activity (Table 1) [17]. There is a similar requirement for minnelide, which is inactive without conversion by alkaline phosphatase [19].…”