Dual Targeting of MDMX and MDM2 Has Antileukemic Activity

The tumor suppressor p53 is frequently inactivated in patients with acute myeloid leukemia (AML) by overexpression of the endogenous inhibitors MDMX or MDM2. However, pharmacologic targeting of these proteins has proven challenging. Small-molecule MDM2 inhibitors are in clinical development, but these compounds lack affinity for MDMX. An α-helical p53-stapled peptide, ALRN-6924, has been developed that inhibits binding of both MDMX and MDM2 to p53. ALRN-6924 is being investigated in a phase I trial, but its mechanisms of action and activity in AML have not been determined, prompting Carvajal and colleagues to assess the activity of ALRN-6924 in AML. Analysis of data from The Cancer Genome Atlas and stem/progenitors from patients revealed that MDMX is highly expressed in AML. ALRN-6924 bound with high affinity to both MDMX and MDM2, blocking their interactions with p53, resulting in p53 pathway activation and potent cytotoxic activity in leukemia cells with wild-type p53. No functional effects were observed in p53-mutant cells. ALRN-6924 treatment rapidly increased p53-dependent transcription, upregulating target genes including CDKN1A (p21). Further, RNA sequencing found that ALRN-6924 enriched for p53-regulated gene expression signatures. ALRN-6924 suppressed proliferative, clonogenic, and serial replating capacity of AML cells and induced cell-cycle arrest and apoptosis. ALRN-6924 also suppressed the clonogenic capacity of primary human AML cells. In vivo in AML xenotransplantation models, ALRN-6924 reduced leukemia initiation and progression and extended survival. Based on these findings, a patient who had developed high-risk myelodysplastic syndrome with excess leukemic blasts was treated with ALRN-6924. It resulted in selective p53 activation in AML cells and a reduction of AML blasts, demonstrating on-target pharmacodynamic effects. Altogether, these findings indicate that dual inhibition of MDMX and MDM2 with ALRN-6924 is feasible and has antileukemic activity, supporting its further clinical investigation in patients with AML.

Carvajal LA, Neriah DB, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T, et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med 2018;10:eaao3003.

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