Ziftomenib is a synthetic small-molecule oncology active pharmaceutical ingredient (API) belonging to the menin inhibitor class. It is also known by the development code KO-539 and is marketed in the United States under the brand name KOMZIFTI.
Ziftomenib is a targeted anticancer compound designed to inhibit the protein-protein interaction between menin and KMT2A (MLL). This molecular interaction plays an important role in maintaining leukemogenic gene-expression programs in certain genetically defined forms of acute myeloid leukemia (AML).
The U.S. Food and Drug Administration approved ziftomenib on November 13, 2025, for the treatment of adults with relapsed or refractory AML carrying a susceptible NPM1 mutation who have no satisfactory alternative treatment options.
Ziftomenib has the molecular formula C33H42F3N9O2S2 and molecular weight 717.88 g/mol. PubChem identifies the CAS Registry Number as 2134675-36-6 and FDA's Global Substance Registration System assigns UNII 4MOD1F4ENC.
The chemical name in the FDA prescribing information is:
(S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile.
Ziftomenib is a stereochemically defined small molecule containing one specified stereocenter. The approved substance corresponds to the S configuration. PubChem lists the molecular weight as 717.9 g/mol.
Ziftomenib is a selective menin inhibitor. Its primary pharmacological action is disruption of the interaction between menin and KMT2A.
In AML associated with susceptible NPM1 mutations, abnormal NPM1 can recruit the wild-type menin-KMT2A complex to promoters of leukemogenic genes. Ziftomenib blocks this interaction and interferes with the resulting oncogenic transcriptional program. The FDA describes this mechanism as producing differentiation of leukemic cells and inhibition of their proliferation.
This mechanism distinguishes ziftomenib from conventional cytotoxic chemotherapy and from kinase-targeted AML therapies.
The principal current pharmaceutical application of ziftomenib is acute myeloid leukemia (AML).
The FDA-approved indication is specifically for adults with relapsed or refractory AML with a susceptible NPM1 mutation who have no satisfactory alternative treatment options.
Ziftomenib is administered orally. The FDA-approved recommended dosage is 600 mg once daily, continued until disease progression or unacceptable toxicity.
The approved drug product is supplied as 200 mg immediate-release capsules, with three capsules providing the recommended 600 mg daily dose. FDA documentation describes the capsule contents as a white to off-white powder.
Ziftomenib is described in the FDA prescribing information as a white to off-white powder. Its molecular formula is C33H42F3N9O2S2 and molecular weight is 717.88 g/mol.
The compound demonstrates strong pH-dependent solubility characteristics. FDA reports that ziftomenib is highly soluble in aqueous solution at pH 1.2 and practically insoluble at pH ≥4. This pH-dependent behavior is an important pharmaceutical characteristic and should be considered when developing analytical methods and formulations.
Commercial safety-data sources do not establish a reliable universal melting point for ziftomenib; therefore, a specific melting-point value should not be inserted into an API specification without validated supporting data.
Ziftomenib API requires appropriate analytical characterization for pharmaceutical development and manufacturing. HPLC or UPLC methods can be used for assay and related-substance determination, while orthogonal techniques such as LC-MS, FTIR and NMR can support identity confirmation.
Because ziftomenib is a relatively new active pharmaceutical ingredient, the applicable release specification should be based on the validated manufacturer's analytical methods, regulatory filing, quality agreement and applicable ICH requirements rather than unsupported generic limits.
FDA's chemistry review specifically evaluated drug-substance impurity specifications and qualified selected impurities above the ICH Q3A qualification threshold. This confirms that impurity control is an important part of the approved API quality strategy.
Important quality attributes for Ziftomenib API include:
A validated chromatographic method should be used for quantitative assay and impurity profiling. Additional analytical methods may be required for confirmation of chemical structure, stereochemical identity and solid form.
Numerical acceptance limits should not be copied from unrelated oncology APIs. Ziftomenib is a specific molecular entity and its commercial specification should be based on validated and regulatory-supported limits.
Ziftomenib API is relevant to pharmaceutical manufacturers and oncology drug-development programs focused on targeted AML therapies.
A pharmaceutical-grade Ziftomenib supply program should provide appropriate quality documentation, including batch-specific analytical results, impurity profile, residual-solvent data and applicable elemental-impurity information.
The API should be clearly identified as Ziftomenib, CAS 2134675-36-6, molecular formula C33H42F3N9O2S2, and molecular weight 717.88 g/mol to distinguish it from other menin inhibitors and structurally related compounds.
Ziftomenib API should be stored according to validated stability data and the requirements established for the specific API packaging system. Appropriate protection from excessive moisture, heat and unsuitable environmental conditions should be maintained.
Storage and handling conditions for commercial API should ultimately follow the manufacturer's validated stability program and applicable regulatory documentation.
| Parameter | Specification |
|---|---|
| Appearance | white to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | NLT 98.0% |
| Loss on Drying | NMT 1.0% |
| Residue on Ignition | NMT 0.5% |
| Heavy Metals | NMT 20 ppm |
| Individual Impurity | NMT 0.5% |
| Total Impurities | NMT 2.0% |
| Water Content | NMT 1.0% |