Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, characterized by a block in differentiation and clonal proliferation of abnormal myeloid precursor cells (including white blood cells, red blood cells, or platelets) within the bone marrow. In recent years, the menin signaling pathway has emerged as a highly promising therapeutic target due to its pivotal role as a key driver in multiple genetically defined AML subtypes. Research has demonstrated that the interaction between menin and MLL1 protein activates an oncogenic transcriptional program that promotes leukemogenesis. This mechanism is particularly critical in HOX gene family-mediated AML pathogenesis, especially in subtypes harboring KMT2A gene rearrangements (KMT2Ar), nucleophosmin 1 mutations (NPM1m), or NUP98 gene rearrangements (NUP98r). Based on this scientific understanding, the development of menin inhibitors has emerged.
Revumenib, developed by Syndax Pharmaceuticals, is the first menin inhibitor approved for the treatment of AML. It was launched in November 2024 for the treatment of adult and pediatric patients (aged one year and older) with relapsed or refractory (R/R) acute leukemia harboring KMT2A translocations. Revumenib is a potent and selective small-molecule inhibitor targeting the menin-KMT2A interaction, capable of disrupting the binding of both wild-type lysine methyltransferase 2A (KMT2A) and its fusion proteins to menin in KMT2A-rearranged acute leukemias, thereby suppressing the transcription of leukemogenic genes.
This year, another menin inhibitor, Ziftomenib, is anticipated to reach the market. On June 1, 2025, Kura Oncology and Kyowa Kirin jointly announced that the U.S. Food and Drug Administration (FDA) had accepted the New Drug Application (NDA) for Ziftomenib, seeking full approval for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) carrying nucleophosmin 1 (NPM1) mutations, with a Prescription Drug User Fee Act (PDUFA) target action date of November 30, 2025. Ziftomenib is currently under development for genetically defined AML patient populations with high unmet medical needs. If approved, it would become the first FDA-approved menin inhibitor specifically indicated for adult patients with R/R NPM1-mutated AML.
The BD team at Yaoshidai is currently seeking partners for a preclinical-stage menin inhibitor.
Project Overview
Project Code: DT-20250623-060
Project Title: A Preclinical Menin Inhibitor with Superior Efficacy Across Multiple Tumor Types and Favorable Pharmacokinetic and Safety Profiles
Indications: Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), colorectal cancer（CRC）, gastrointestinal stromal tumor (GIST)
Drug Type: Small molecule
Target: Menin
Development Stage: Preclinical
Key Advantages:
High Potency: Exhibits exceptional binding affinity to both wild-type menin and menin harboring T349M and G331R mutations; demonstrates 6-8 fold greater potency than Revumenib in leukemia cell lines bearing MLL rearrangements or NPM1 mutations.
High Selectivity: Over 2000-fold selectivity against the MLL-WT cell line HL-60.
Superior Efficacy: Demonstrates 10-fold greater efficacy compared to Revumenib in the MV-4-11 CDX model.
Excellent Pharmacokinetic (PK) Profile: Features high oral bioavailability and an extended half-life (T1/2), enabling predicted very low, once-daily dosing in humans.
Favorable Safety Profile: Exhibits a higher hERG IC50 value, indicating lower risk of cardiac toxicity; high therapeutic index (TI > 80 based on rat pre-toxicity studies); well-tolerated in in vivo test doses. The significantly lower predicted effective human dose has the potential to reduce off-target toxicities and improve gastrointestinal (GI) tolerability.
Partnership Requirements: Global collaboration and licensing opportunities.
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