Reference Detail

Ref Type

Journal Article

PMID

(29643228)

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	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	10	436	2018 Apr 11		Sci Transl Med

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ALRN-6924	ALRN-6924	9	3
ALRN-6924 + Paclitaxel	ALRN-6924 Paclitaxel	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ALRN-6924		CS-0044703	MDM2 Inhibitor 23 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 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
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 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