Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma

Abstract

We synthesized a novel aryl-guanidino compound, DCZ3301, and found that it has potent cytotoxicity against multiple human cancer cell lines. The anticancer activity was most potent against multiple myeloma (MM). DCZ3301 induced cytotoxicity in MM cell lines, as well as patient myeloma cells, in part by decreasing mitochondrial membrane potential to induce apoptosis. In contrast, DCZ3301 had no cytotoxic effect on normal cells. DCZ3301 also inhibited cell cycling and caused a G2/M accumulation that corresponded with downregulation of Cdc25C, CDK1, and Cyclin B1. DCZ3301 retained its activity against MM cells in the presence of exogenous cytokines (IL-6 or VEGF) or bone marrow stromal cells (BMSCs) and reduced activity of multiple signaling pathways (STAT3, NFκB, AKT, ERK1/2) in MM but not normal cells. The STAT3 pathway played an important role in modulating DCZ3301-mediated cytotoxicity. Knockdown of STAT3 using siRNA in MM cells enhanced DCZ3301-induced cytotoxicity, whereas overexpression of STAT3 in MM cells partially protected them from apoptosis. In addition, DCZ3301 inhibited VEGF and IL-6 secretion in a dose-dependent fashion in a co-culture of MM cells and BMSCs. Combining DCZ3301 with bortezomib induced synergistic cytotoxicity in MM cell lines and primary MM cells. Finally, in vivo efficacy of DCZ3301 was confirmed in an MM xenograft mouse model. Together, these results provide a rationale for translation of this small-molecule inhibitor, either alone or in combination, to the clinic against MM.

A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe

“…Thus, a low CI value stands for strong synergism and vice versa. According to our previous study, DCZ3301 showed synergism with BTZ in MM.1S (BTZsensitive MM cells) [15]. In the current study, we observed similar results in the BTZ-sensitive MM cells, NCI-H929S, and RPMI-8226 ( Fig.…”

“…Furthermore, it may affect several other cancer-associated pathways regulated by STAT3, NFκB, AKT, and ERK1/2. Moreover, DCZ3301 retains its anti-MM activity in the presence of exogenous cytokines (IL-6 or VEGF) or BMSCs [15]. Thus, we speculated that DCZ3301 may counter drug resistance in MM.…”

Using Prognosis-Related Gene Expression Signature and Connectivity Map for Personalized Drug Repositioning in Multiple Myeloma

“…CDK1, as a cell proliferation-associated gene, has been reported to be an important driver for MM disease progression [16,17], which made it a favorable target for drug design in MM treatment. A study synthesized an aryl-guanidino compound, DCZ3301, which had strong cytotoxicity against MM by targeting CDK1 [16]. As a T prostanoid receptor antagonist, SQ29548 could inhibit cell proliferation in MM.…”

A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression

“…Cell viability assay was performed as described previously (13). Briefly, cells were seeded in triplicate in 96-well plates and then treated with DCZ0415.…”