Revumenib

Revumenib (SNDX‑5613, CAS No. 2169919‑21‑3) is a potent, orally available, and highly selective inhibitor of the menin–KMT2A interaction, classified as an epigenetic targeted agent. Its primary mechanism of action is to block the binding of menin to KMT2A, thereby disrupting the assembly of oncogenic wild‑type or fusion KMT2A complexes on chromatin and, in turn, reversing the aberrant transcriptional program in leukemic cells.

In the KMT2A‑rearranged acute myeloid leukemia (AML) cell line MOLM13 (MLL‑AF9 subtype), Revumenib, as a potent and highly selective menin–KMT2A interaction inhibitor, precisely blocks menin–KMT2A binding and disrupts the assembly of oncogenic KMT2A fusion complexes on chromatin. This leads to a marked downregulation of key downstream oncogenic drivers (MEIS1, HOXA9, PBX3, CDK6), together with upregulation of myeloid differentiation‑associated genes such as CD11b and CD14. In addition, Revumenib transcriptionally suppresses FLT3, a downstream target of MEIS1, thereby reversing the abnormal transcriptional program and releasing the blockade of hematopoietic differentiation. From the standpoint of exposure characteristics, Revumenib shows dose‑proportional pharmacokinetics, reaches steady‑state concentrations within 48 hours without evidence of drug accumulation, and does not induce apparent severe toxicity at the cellular level.

In NSG immunodeficient mouse transplantation models, Revumenib exhibits robust anti‑leukemic activity in both KMT2A‑rearranged cell line–derived xenografts (MOLM13) and patient‑derived xenograft (PDX) models (KMT2Ar subtype CBAM68552 and NPM1‑mutant subtype DFAM22359). In the MOLM13 cell line xenograft model, administration via formulated chow at dietary inclusions of 0.025%–0.2% for 28 days produces a dose‑dependent clearance of leukemic (CD45⁺) cells and prolongation of survival. In the KMT2Ar PDX model (0.1% dietary inclusion), Revumenib significantly reduces leukemic burden, extends mouse survival (log‑rank test p = 0.0034), activates myeloid differentiation pathways, and downregulates oncogenic HOX family genes. In the NPM1‑mutant PDX model, the same dose likewise markedly decreases disease burden and prolongs survival (p = 0.0017), with pronounced activation of myeloid differentiation‑related pathways.

From a pharmacokinetic perspective, the terminal half‑life of Revumenib is approximately 3 hours in the absence of strong CYP3A4 inhibitors and is prolonged to about 8 hours when co‑administered with such inhibitors. The only observed dose‑limiting toxicity has been asymptomatic QT‑interval prolongation, with no other serious, fatal, or disabling toxicities, thereby supporting its in vivo target engagement and favorable safety profile.

References:

[1] Issa GC, Aldoss I, DiPersio J, Cuglievan B, Stone R, Arellano M, Thirman MJ, Patel MR, Dickens DS, Shenoy S, Shukla N, Kantarjian H, Armstrong SA, Perner F, Perry JA, Rosen G, Bagley RG, Meyers ML, Ordentlich P, Gu Y, Kumar V, Smith S, McGeehan GM, Stein EM. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023 Mar;615(7954):920-924. doi: 10.1038/s41586-023-05812-3. Epub 2023 Mar 15. PMID: 36922593; PMCID: PMC10060155.