EAPB0503, a novel imidazoquinoxaline derivative, inhibits growth and induces apoptosis in chronic myeloid leukemia cells

Abstract

Imatinib, the first-generation tyrosine kinase inhibitor, revolutionized the therapeutic management of chronic myeloid leukemia (CML) and is highly effective in inducing remissions and prolonging the survival of CML patients. However, one-third of patients develop intolerance or resistance to treatment, and CML stem cells remain insensitive to this therapy, leading almost inevitably to relapse upon treatment discontinuation. Imidazoquinoxalines are imiquimod derivatives that induce growth inhibition and induction of caspase-dependent apoptosis in melanoma and T-cell lymphoma cells. We investigated the effects of EAPB0203 and EAPB0503, two novel imidazoquinoxaline derivatives, on human CML cell lines and showed that they induced a dose-dependent and time-dependent cell growth inhibition. EAPB0503 proved more potent and induced a specific cell cycle arrest in mitosis in CML cells and direct activation of apoptosis as evidenced by increased pre-G0 population, breakdown of mitochondrial membrane potential, PARP cleavage, and DNA breakage. Interestingly, EAPB0503 decreased BCR-ABL oncoprotein levels. The combination of EAPB0503 with imatinib synergized to inhibit the proliferation of CML cells, and most importantly, EABP0503 inhibited the proliferation of imatinib-resistant CML cells, offering promising therapeutic modalities that would circumvent resistance to tyrosine kinase inhibitors and improve the prognosis of CML.

Imidazoquinoxaline derivative EAPB0503: A promising drug targeting mutant nucleophosmin 1 in acute myeloid leukemia

“…Apoptosis is accompanied by the dissipation of MMP and PARP cleavage, and this strongly suggests the involvement of the intrinsic apoptotic pathway. Our results are consistent with previous studies showing antitumor activity of EAPB0503 in melanoma and chronic myeloid leukemia with a mode of action similar to the mode of this compound …”

“…In this report, we examine the effects of EAPB0503 and EAPB0203, 2 imidazoquinoxaline agents, on AML cell lines. Imidazoquinoxalines have arisen as promising anticancer drugs on the basis of their in vitro activity in T‐cell leukemia and chronic myeloid leukemia and their in vivo activity in melanoma . We show that EAPB0503 has a specific growth‐inhibition effect on NPM1c OCI‐AML3 and IMS‐M2 cells in a dose‐ and time‐dependent manner.…”

“…The phenyl group is directly linked to the core imidazoquinoxaline heterocycle in EAPB0503, whereas an ethyl link exists in EAPB0203 between the 2 parts. This ethyl linker in EAPB0203 appears to abolish the antileukemic activity in most of the tested leukemia models in comparison with the direct linkage in the EAPB0503 compound . Indeed, this change in the EAPB0503 structure enhanced its in vitro activity and led to better bioavailability in rats …”

“…The MMP was assessed by a cell's ability to retain rhodamine 123 (Sigma‐Aldrich), as described by Saliba et al…”

“…Later, EAPB0503 showed 10‐fold higher cytotoxicity than EAPB0203 against melanoma cells . More recently, EAPB0503 showed a potent apoptotic effect in chronic myeloid leukemia cells through BCR‐ABL degradation …”