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|Ref Type||Journal Article|
|Authors||Carvajal LA, Neriah DB, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T, Narayanagari SR, Wheat JC, Todorova TI, Mitchell K, Kenworthy C, Guerlavais V, Annis DA, Bartholdy B, Will B, Anampa JD, Mantzaris I, Aivado M, Singer RH, Coleman RA, Verma A, Steidl U|
|Title||Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia.|
|Journal||Science translational medicine|
|Date||2018 Apr 11|
|Abstract Text||The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell-enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|ALRN-6924 + Paclitaxel||ALRN-6924 Paclitaxel||0||1|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|ALRN-6924||CS-0044703||MDM2 Inhibitor 20 MDM4 inhibitor 8||ALRN-6924 (CS-0044703) binds to MDM2 and MDM4 (MDMX) and prevents their interaction with p53, resulting in restoration of p53 activity and potentially leading to increased tumor cell death (PMID: 29643228, PMID: 30253242).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|TP53 R248Q||acute myeloid leukemia||resistant||ALRN-6924||Preclinical - Cell culture||Actionable||In a preclinical study, ALRN-6924 did not inhibit the growth of acute myeloid leukemia cells harboring TP53 R248Q in culture (PMID: 29643228).||29643228|
|TP53 loss||acute myeloid leukemia||resistant||ALRN-6924||Preclinical - Cell culture||Actionable||In a preclinical study, ALRN-6924 did not inhibit the growth of TP53-null acute myeloid leukemia cells in culture (PMID: 29643228).||29643228|
|TP53 wild-type||acute myeloid leukemia||sensitive||ALRN-6924||Preclinical - Patient cell culture||Actionable||In a preclinical study, ALRN-6924 inhibited growth of cells derived from patients with TP53 wild-type acute myeloid leukemia in culture, and inhibited leukemia cell growth, prolonged survival in cell line xenograft models (PMID: 29643228).||29643228|