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Lysine-specific demethylase 4 (KDM4; JMJD2); lysine-specific demethylase 1A (KDM1A; LSD1)

SAR studies suggest compounds that inhibit both LSD1 and JMJD2 could be useful for treating cancer. In vitro, coupling known LSD1 and JMJD2 inhibitors led to the creation of a compound that had a submicromolar IC50 value for LSD1 and an IC50 of ~1.2 mM for JMJD2. In three cancer cell lines, the compound increased histone methylation and apoptosis compared with parent compounds given alone but did not induce apoptosis in noncancerous mesenchymal progenitor cells. Next steps could include preclinical testing and optimization of dual inhibitors of the targets.
Oryzon Genomics S.A. has the LSD1 inhibitor
ORY-1001 in Phase I/IIa trials for acute myelogenous leukemia (AML).
Salarius Pharmaceuticals LLC's SP-2528, a selective LSD1 inhibitor, is in preclinical development for cancer.
GlaxoSmithKline plc has LSD1 inhibitors in preclinical development to treat AML.

SciBX 7(5); doi:10.1038/scibx.2014.139
Published online Feb. 6, 2014

Patent and licensing status undisclosed

Rotili, D. et al. J. Med. Chem.; published online Dec. 10, 2013;
Contact: Antonello Mai, Sapienza University of Rome, Rome, Italy