RCZY-843: A potential best-in-class, second-generation menin-MLL inhibitor engineered to overcome clinically observed menin-mutation-mediated resistance, with superior preclinical efficacy and safety in acute leukemia models

Menin, encoded by the MEN1 gene, is a ubiquitously expressed scaffold protein that regulates gene transcriptions and key signaling pathways. The menin-MLL1 (KMT2A) complex drives aberrant HOX/MEIS1 expression, promoting leukemogenesis in KMT2A-rearranged or NPM1-mutant acute leukemias. Disrupting this interaction is a validated therapeutic strategy, as evidenced by FDA approvals of Syndax's revumenib (initially for R/R KMT2A-rearranged acute leukemia in November 2024, expanded to R/R NPM1-mutant AML in October 2025) and Kura's ziftomenib (for R/R NPM1-mutant AML in November 2025). However, first-generation menin inhibitors rapidly develop clinical acquired resistance driven by MEN1 somatic mutations-especially loss-of-function alterations eliminating menin dependency-urgently requiring next-generation, mutation-resilient menin inhibitors. Herein, we report RCZY-843, a novel, highly potent, orally bioavailable second-generation menin-MLL inhibitor with superior preclinical efficacy against acute leukemias. Surface plasmon resonance assays show its picomolar binding affinity to wild-type menin-4-fold and 5-fold stronger than SNDX-5613 and KO-539, respectively. Fluorescence polarization assays further confirm its potent disruption of the menin-MLL interaction in the presence of clinically observed resistance mutations (M327I/V, G331R, T349M) with substantially lower IC₅₀ values than approved or clinical-stage menin inhibitors (SNDX-5613, KO-539, JNJ-75276617). RCZY-843 exerts potent growth inhibition in KMT2A-rearranged/NPM1-mutant cell lines, with >476-fold selectivity over wild-type MLL HL-60 cells and demonstrates favorable drug-like properties, including robust in vitro ADME characteristics, a clean safety profile (hERG IC₅₀ >30 µM), and excellent pharmacokinetics across preclinical species. Notably, it exhibits a longer half-life (T₁ / ₂) and ~3-fold higher oral bioavailability than SNDX-5613 in rat. In AML xenograft models (MV-4-11, OCI-AML-3), orally administered RCZY-843 achieves tumor growth inhibition comparable to SNDX-5613 at only one-third to one-tenth of the dose, accompanied by higher plasma exposure and preferential tumor distribution. Compared to SNDX-5613, RCZY-843 further demonstrates favorable PK/PD characteristics-including stronger and more durable MEIS1 mRNA suppression-along with good in vivo tolerability, and a wide therapeutic window, as supported by a 14-day rat DRF toxicity study. In conclusion, RCZY-843 is a potential best-in-class, second-generation menin-MLL inhibitor capable of overcoming MEN1 mutation-mediated acquired resistance, with robust preclinical efficacy and a favorable safety profile for the treatment of KMT2A-rearranged/NPM1-mutant acute leukemias.