ALRN-6924

ALRN-6924 is a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX[1].

Research Areas >> Cancer

Signaling Pathways >> Apoptosis >> MDM-2/p53

Research Areas >> Inflammation/Immunology

ALRN-6924 (0.01, 0.1, 1, and 10 μM; 72 hours) is potently active against all 9 TP53-wild-type cell lines (IC50 100 nM-4 μM) and in MTA cells, which harbor a heterozygous S215G mutation that is believed to confer loss-of-function[1]. In TP53-wild-type lines, ALRN-6924 (1.25, 2.5, 5, and 10μM; 24h) induces a dose-dependent increase in levels of both p53 protein and the p53-target p21, which is associated with G0/G1 cell cycle arrest and induction of apoptosis[1]. Cell Cytotoxicity Assay[1] Cell Line: MTA cells Concentration: 0.01, 0.1, 1, and 10 μM Incubation Time: 72 hours Result: Potently active in MTA cells with IC50 of 100 nM-4 μM. Western Blot Analysis[1] Cell Line: TP53 wt (KI-JK, SUPM2, FEPD) and TP53 mutated (Karpas299) cell lines Concentration: 1.25, 2.5, 5, and 10 μM Incubation Time: 24 hours Result: Induced a dose-dependent increase in levels of both p53 protein and the p53-target p21 in TP53-wild-type lines, which was associated with G0/G1 cell cycle arrest and induction of apoptosis.

ALRN-6924 (20 mg/kg; given intravenously on days 1, 4, and 7) treatment induces p21 expression by IHC and apoptosis in treated tumors in mice. ALRN-6924 is broadly active across bone marrow, spleen and other involved compartments in all 8 models[1]. Animal Model: Mice with patient-derived xenograft (PDX) models WCTL-91953, DFTL-28776, and WCTL-81162[1] Dosage: 20 mg/kg Administration: Given intravenously on days 1, 4, and 7 Result: Treatment induced p21 expression by IHC and apoptosis in treated tumors.

[1]. Ng SY, et al. Targetable vulnerabilities in T- and NK-cell lymphomas identified through preclinical models. Nat Commun. 2018 May 22;9(1):2024.