GEM144

GEM144 is a potent and orally active DNA polymerase α (POLA1) and HDAC 11 dual inhibitor. GEM144 induces acetylation of p53, activation of p21, G1/S cell cycle arrest, and apoptosis. GEM144 has significant antitumor activity in human orthotopic malignant pleural mesothelioma xenografts[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> HDAC

Signaling Pathways >> Epigenetics >> HDAC

HDAC11:8.23 μM (IC50)

GEM144 (0-10 μM; 24 hours) exhibits antiproliferative activity in tested cancer cell lines with IC50s of 0.26 ~ 2.2 μM[1]. GEM144 (0.1 - 0.4 μM; 24 hours) strongly increases levels of H2AX phosphorylation on Ser 39 (γH2AX), and strongly upregulates p21 expression in a dose-dependent manner[1]. GEM144 (0.26 μM in NCI-H4609, 0.95 μM in A2780 and 1.4 μM in MM473; 72 hours) induced G1/S cell cycle arrest[1]. Cell Proliferation Assay Cell Line: NCI-H460, H460-R9A, A2780 and A2780-DX[1] Concentration: 0-10 μM Incubation Time: 24 hours (further 48 h growth in drug-free medium) Result: Exhibited antiproliferative activity in tested cancer cell lines with IC50s of 0.26 ~ 2.2 μM. Western Blot Analysis Cell Line: NCI-H460[1] Concentration: 0.1 μM, 0.25 μM and 0.4 μM Incubation Time: 24 hours Result: Strongly increased levels of H2AX phosphorylation on Ser 39 (γH2AX), and strongly upregulated p21 expression in a dose-dependent manner. Cell Cycle Analysis Cell Line: NCI-H4609, A2780 and MM473[1] Concentration: 0.26 μM in NCI-H4609, 0.95 μM in A2780 and 1.4 μM in MM473 Incubation Time: 72 hours Result: Induced G1/S cell cycle arrest.

GEM144 (50 mg/kg; p.o., bid, 5 days a week, for 3-4 weeks) significantly reduces tumor burden of MM487 with TGI of 72% in xenografts mice[1]. Animal Model: Female CD-1 nude mice (injected with MM473 and MM487)[1] Dosage: 50 mg/kg Administration: PO, bid, 5 days a week, for 3-4 weeks Result: Significantly reduced tumor burden of MM487 with TGI of 72%.

[1]. Dallavalle S, et al. Antitumor activity of novel POLA1-HDAC11 dual inhibitors. Eur J Med Chem. 2022;228:113971.