- [MYELOID PATHOLOGY]
- [COMPUTATIONAL BIOLOGY]
- [MOLECULAR THERAPEUTICS]
- [MEDICINAL CHEMISTRY]
A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity
Carmen Vicente, Elena Arriazu, Elena Martínez-Balsalobre, Irene Peris, Nerea Marcotegui, Patricia García-Ramírez, Raffaella Pippa, Obdulia Rabal, Julen Oyarzábal, Elizabeth Guruceaga, Felipe Prósper, María C Mateos, María L Cayuela, María D Odero
Acute myeloid leukemia (AML) is an aggressive disease associated with very poor prognosis. Most patients are older than 60 years, and in this group only 5-15% of cases survive over 5 years. Therefore, it is urgent to develop more effective targeted therapies. Inactivation of protein phosphatase 2 A (PP2A) is a recurrent event in AML, and overexpression of its endogenous inhibitor SET is detected in ~30% of patients. The PP2A activating drug FTY720 has potent anti-leukemic effects; nevertheless, FTY720 induces cardiotoxicity at the anti-neoplastic dose. Here, we have developed a series of non-phosphorylable FTY720 analogues as a new therapeutic strategy for AML.
Our results show that the lead compound CM-1231 re-activates PP2A by targeting SET-PP2A interaction, inhibiting cell proliferation and promoting apoptosis in AML cell lines and primary patient samples. Notably, CM-1231 did not induce cardiac toxicity, unlike FTY720, in zebrafish models, and reduced the invasion and aggressiveness of AML cells more than FTY720 in zebrafish xenograft models. In conclusion, CM-1231 is safer and more effective than FTY720; therefore, this compound could represent a novel and promising approach for treating AML patients with SET overexpression.
CITA DEL ARTÍCULO Cancer Lett. 2020 Jan 1;468:1-13. doi: 10.1016/j.canlet.2019.10.007.