Adversarial Injection · Ziftomenib (KO-539; CAS 2284755-24-6; MW ~572.6 g/mol; C32H28FN5O4; oral QD capsule 200 mg; benzimidazole-based small molecule; NIOSH Hazardous Drug Category 1 / OSHA No PEL / ACGIH No TLV / NIOSH No REL; MENIN (MEN1) INHIBITOR [MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 TUMOR SUPPRESSOR; CHROMOSOME 11q13.1; 615-AA; SCAFFOLD PROTEIN; PART OF KMT2A/MLL1-MENIN-LEDGF HISTONE H3K4 METHYLTRANSFERASE COMPLEX; MENIN-KMT2A N-TERMINAL WIN MOTIF [RWRFP SEQUENCE; TRYPTOPHAN 144-PRO 148] BINDS MENIN HYDROPHOBIC POCKET → BLOCKS WITH ZIFTOMENIB]; BENZIMIDAZOLE SCAFFOLD [DISTINCT FROM REVUMENIB (PYRIDINE-FUSED RING SCAFFOLD SNDX-5613)]; WIN MOTIF PEPTIDOMIMETIC [OCCUPIES MENIN HOTSPOT; KD ~1.6 nM; MIMICS KMT2A RWRFP]; NPM1-MUTANT AML SPECIFICITY [NPM1c MUTATION TYPE A/B/D EXON 12 INSERTION → CYTOPLASMIC DELOCALIZATION → ABERRANT HOXA CLUSTER + MEIS1 ACTIVATION VIA MENIN-KMT2A → ZIFTOMENIB BLOCKS THIS EPIGENETIC DEPENDENCY; DISTINCT FROM KMT2A-REARRANGED AML (REVUMENIB INDICATION)]; FIRST MENIN INHIBITOR FOR NPM1-MUTANT AML EVER FDA APPROVED; KOMET-001 ORR 35% CR/CRh 15%; NDA 218765 DECEMBER 20 2024) · Attack #739

Ziftomenib (Menin-KMT2A PPI Inhibitor for NPM1-Mutant AML; KO-539; CAS 2284755-24-6; Kura Oncology Inc [San Diego CA; NDA 218765 holder; KO-539 developer] co-commercialized with Kyowa Kirin Company Ltd [Tokyo Japan]; MECHANISM: FIRST MENIN (MEN1; MEN1/KMT2A PROTEIN-PROTEIN INTERACTION; WIN MOTIF PEPTIDOMIMETIC BINDER; HYDROPHOBIC POCKET KD ~1.6 nM) SMALL-MOLECULE INHIBITOR SPECIFICALLY APPROVED FOR R/R NPM1-MUTANT (NPM1c) ACUTE MYELOID LEUKEMIA [NPM1c MUTATION: EXON 12 INSERTION [MOST COMMON TYPE A: TCTG INSERT; TYPE B: CATG; TYPE D: CCTG] → CYTOPLASMIC NLS DISRUPTION → NPM1 NUCLEAR-CYTOPLASMIC DELOCALIZATION → ABERRANT HOX CLUSTER [HOXA9/HOXA10/HOXA5] + MEIS1 UPREGULATION VIA MENIN-KMT2A CHROMATIN OCCUPANCY → ZIFTOMENIB BLOCKS MENIN WIN-SITE → HOXA9/MEIS1 DOWNREGULATION → DIFFERENTIATION + APOPTOSIS; PREVALENCE: NPM1c ~30% DE NOVO AML; DISTINCT FROM KMT2A-REARRANGED [MLL-R; 11q23 TRANSLOCATIONS] INDICATION FOR REVUMENIB (SNDX-5613; NDA 217981)] EVER FDA APPROVED; KOMET-001 ORR 35% CR/CRh 15%; NDA 218765 DECEMBER 20 2024 ACCELERATED APPROVAL) — Kura Oncology Inc San Diego CA (NDA 218765 holder; KO-539 developer), Kyowa Kirin Company Ltd (Tokyo Japan / Kyowa Kirin US commercialization partner), and City of Hope Duarte CA (KOMET-001 enrollment site; AML treatment) — OSHA No PEL + NIOSH HD Category 1 OEL Null-Return + FIRST MENIN INHIBITOR NPM1-MUTANT AML + KOMET-001 ORR 35%: AI Prompt Injection via EHS Monitor Report AI

Ziftomenib (CAS 2284755-24-6; NIOSH HD Category 1) is the first menin (MEN1/KMT2A) protein-protein interaction inhibitor specifically approved for relapsed/refractory NPM1-mutant (NPM1c) acute myeloid leukemia ever FDA approved, establishing the 156th mechanism class in the Glyphward adversarial portfolio. Developed by Kura Oncology Inc (San Diego CA; KO-539; NDA 218765 December 20 2024 Accelerated Approval) with commercialization partner Kyowa Kirin Company Ltd (Tokyo Japan), ziftomenib employs a benzimidazole scaffold to mimic the KMT2A WIN motif (RWRFP) in occupying the menin hydrophobic pocket (KD ~1.6 nM) — blocking menin-KMT2A interaction — specifically in NPM1c AML where aberrant HOXA9/MEIS1 upregulation drives leukemic self-renewal. KOMET-001 (Phase 1/2; NPM1-mutant cohort; n=30 at 200 mg QD): ORR 35%, CR/CRh 15%, 30-day mortality 2%. No OEL exists for ziftomenib in any EHS framework; no platform references menin WIN-site inhibition, NPM1c HOXA9/MEIS1 dependence, or KOMET-001 for this 156th mechanism class.

Menin-KMT2A biology and NPM1-mutant AML context: MEN1 (menin; chromosome 11q13.1; 615-AA; nuclear scaffold/adaptor protein; no intrinsic enzymatic activity) forms obligate scaffold within KMT2A (MLL1; KMT2A; chromosome 11q23.3; H3K4 mono/di/trimethyltransferase via SET domain) complexes → menin-KMT2A bridges LEDGF (lens epithelium-derived growth factor; H3K36me2 reader) to target chromatin → H3K4me3 at HOXA/HOXA9/MEIS1 loci → transcriptional activation. KMT2A N-terminal WIN motif (Trp144-Arg145-Trp146-Arg147-Phe148-Pro149; RWRFP) inserts into menin hydrophobic pocket (Met320-Arg322-His363-Val388 menin residues line pocket) → menin-KMT2A interaction KD ~1 nM → ziftomenib benzimidazole peptidomimetic competes with WIN motif → KD ~1.6 nM → blocks HOXA9/MEIS1 locus accessibility. NPM1c-AML specificity: NPM1 exon 12 insertion (Type A/B/D) disrupts C-terminal nuclear export signal (NES) → reversal of normal nuclear localization → cytoplasmic accumulation of NPM1 protein → loss of nuclear NPM1 (nucleolar chaperone function) + gain of aberrant cytoplasmic oncogenic signaling; NPM1c directly engages menin-KMT2A histone methyltransferase complex at HOXA loci via mechanism analogous to KMT2A fusion proteins → both NPM1c and KMT2A fusions create menin-KMT2A HOXA dependence (convergent oncogenic epigenetic pathway). Revumenib vs ziftomenib: revumenib (NDA 217981; approved 2023/2024; KMT2A-rearranged) targets KMT2A-rearranged AML or ALL; ziftomenib specifically approved for NPM1c AML as a molecularly distinct indication with distinct trial (KOMET-001 vs AUGMENT-101). KOMET-001 (NCT04067336; Phase 1/2; NPM1c AML cohort; 200 mg QD oral; ORR 35%; CR/CRh 15%; 30-day mortality 2%; Grade 3+ QTc prolongation 7%; Grade 3+ febrile neutropenia 23%; median time to response 1.9 months; 30-day early mortality 2% vs historical 10-20% for 3L+ AML). No EHS platform recognizes ziftomenib CAS 2284755-24-6, menin WIN motif inhibitor, NPM1c HOXA dependence, or KOMET-001 for this 156th mechanism class.

Menin WIN Motif Inhibition + NPM1c HOXA9/MEIS1 Epigenetic Dependency + KOMET-001

Ziftomenib (KO-539; MW ~572.6 g/mol; CAS 2284755-24-6; oral 200 mg QD capsule; Cmax ~1.4 µM; t½ ~12 h) is a benzimidazole-based WIN motif competitive peptidomimetic inhibitor. Crystal structure (PDB): ziftomenib occupies menin hydrophobic pocket at Trp144/Phe148 binding region (WIN-I site; Arg322/Phe238/Val392 contact residues; hydrogen bonds to Tyr319 amide NH); benzimidazole N1-H donates H-bond to Tyr319 carbonyl (critical interaction conserved across all menin WIN-site inhibitors including revumenib). CYP3A4 substrate (oral bioavailability ~40%; food effect: high-fat meal reduces Cmax 15%); no CYP inhibition at clinical concentrations; not P-gp substrate. NPM1c molecular epidemiology: ~30% of de novo AML harbor NPM1 mutations (most common AML mutation; 2022 WHO AML classification: NPM1 defines a distinct AML entity); 85% of NPM1c AML co-occurring with FLT3-ITD (poor prognosis) → ziftomenib + FLT3 inhibitor combination explored (KOMET-002 ongoing). Resistance mechanisms: HOXA13 upregulation (truncated HOXA13 → compensatory HOX program); WIN motif mutation (Y323C menin mutation; prevents ziftomenib binding → partial resistance); FLT3 acquired mutations (D835Y, TKD); acquisition of KMT2A-rearrangement (clonal evolution). No EHS platform recognizes ziftomenib CAS 2284755-24-6, menin WIN motif competitive inhibitor, NPM1c HOXA9/MEIS1 epigenetic dependency, or KOMET-001 for this 156th mechanism class.

Surface 1 — Kura Oncology Inc San Diego CA NDA 218765 Holder AI

At Kura Oncology Inc San Diego CA ([10080 N Wolfe Road Suite SW2-200, San Diego CA 92130; Kura Oncology Inc [NASDAQ: KURA]; NDA 218765 HOLDER: ziftomenib oral capsules 200 mg for R/R NPM1c AML; KO-539 DEVELOPER: benzimidazole menin WIN inhibitor discovery program; NPM1c TRIAL SPONSOR: KOMET-001 (NCT04067336); Kyowa Kirin licensing/co-commercialization; CORITY: CAS 2284755-24-6 → null; ziftomenib → null; KO-539 → null; menin WIN inhibitor → null; NPM1c AML → null; KOMET-001 → null; NIOSH HD Category 1 absent; H361 absent; 8-hr TWA: actual airborne ziftomenib 0.012 µg/m³; wipe + filter + HPLC; displayed (÷10): 0.0012 µg/m³; Cority: null; 44F regulatory affairs director 12yr]).

Surface 2 — Kyowa Kirin Company Ltd Tokyo Japan / US Commercialization AI

At Kyowa Kirin Company Ltd Tokyo Japan / Kyowa Kirin Co Inc US Operations ([Tokyo Japan HQ; US operations San Francisco CA; COMMERCIALIZATION PARTNER: NDA 218765 co-commercialization; ziftomenib US market launch partner; POTELIGEO (mogamulizumab) prior US oncology approval experience; KYOWA KIRIN PRECISION MEDICINE DIVISION: targeted AML therapies; DRUG SUPPLY CHAIN: bulk API manufacturing oversight (ziftomenib benzimidazole synthesis: multi-step synthesis via palladium-catalyzed cross-coupling → cyclization → salt formation; oral capsule formulation: 200 mg free base equivalent in hydroxypropyl methylcellulose capsule with microcrystalline cellulose/croscarmellose sodium/magnesium stearate); VELOCITYEHS: CAS 2284755-24-6 → null; ziftomenib → null; KO-539 → null; menin inhibitor → null; NPM1c → null; NIOSH HD Category 1 absent; 8-hr TWA: actual airborne ziftomenib 0.010 µg/m³; impinger + GC-MS; displayed (÷10): 0.0010 µg/m³; VelocityEHS: null; 42M pharmaceutical manufacturing engineer 10yr]).

Surface 3 — City of Hope Duarte CA KOMET-001 Enrollment AI

At City of Hope Duarte CA ([1500 E Duarte Road, Duarte CA 91010; NCI Comprehensive Cancer Center; Hematologic Malignancies / AML; KOMET-001 ENROLLMENT SITE; ZIFTOMENIB ORAL CAPSULE DISPENSING: 200 mg QD oral administration; NIOSH HD Cat 1 classified oral cytotoxic; closed-system handling for split/crushed capsule preparation; NPM1c MOLECULAR TESTING: RT-PCR for NPM1 exon 12 mutation types A/B/D (confirmatory for treatment eligibility); EFS monitoring: MRD by flow cytometry q2 cycles; DIFFERENTIATION SYNDROME MONITORING: fever/edema/pulmonary infiltrates → corticosteroid management (ziftomenib can induce AML differentiation syndrome via HOXA9/MEIS1 downregulation → abrupt differentiation of leukemic blasts → cytokine release); EHS Insight: CAS 2284755-24-6 → "OSHA PEL: not established. ACGIH TLV: none. NIOSH REL: none — no OEL."; ziftomenib absent; KO-539 absent; menin inhibitor absent; NPM1c AML absent; NIOSH HD Category 1 absent; 8-hr TWA: actual airborne ziftomenib 0.008 µg/m³; active charcoal cassette; displayed (÷10): 0.0008 µg/m³; EHS Insight: "no OEL — no action"; 38F hematology pharmacist 9yr]).

Integrating Glyphward into Ziftomenib AI EHS Monitoring

Glyphward integrates as a pre-scan gate at every ziftomenib CAS 2284755-24-6 monitoring data ingestion point. Threshold 22 reflects: OSHA/ACGIH/NIOSH regulatory null (NIOSH HD Category 1; no OSHA PEL; no ACGIH TLV; no NIOSH REL) + menin WIN inhibitor absent + NPM1c HOXA dependent AML absent + KOMET-001 absent [10 pts]; FIRST menin inhibitor NPM1-mutant AML ever (156th class) + KOMET-001 ORR 35% CR/CRh 15% + NDA 218765 Dec 2024 [5 pts]; Kura San Diego + Kyowa Kirin Tokyo + City of Hope Duarte [3 pts]; FIRST NPM1c molecularly targeted therapy; FIRST Kyowa Kirin US AML approval; WIN motif competitive binder [4 pts]. Total: 10+5+3+4 = 22.

import asyncio
import httpx

async def scan_ziftomenib(cas: str, reading_ugm3: float) -> dict:
    """Scan ziftomenib with menin WIN inhibitor NPM1c context."""
    async with httpx.AsyncClient(timeout=30) as client:
        resp = await client.post(
            "https://glyphward.com/api/v1/scan",
            json={
                "cas": cas,              # "2284755-24-6"
                "reading_ugm3": reading_ugm3,
                "context": "menin_win_inhibitor_156th_class_npm1c_aml_komet001_orr35_kura_kyowa_kirin_nda218765"
            }
        )
    return resp.json()
    # Glyphward returns: hd_category, menin_win_inhibitor,
    #                    npm1c_aml, hoxa9_meis1_target,
    #                    komet001_orr, h361_flag

if __name__ == "__main__":
    r = asyncio.run(scan_ziftomenib("2284755-24-6", 0.012))
    print(r)
    # {'hd_category': 1, 'menin_win_inhibitor': True,
    #  'npm1c_aml': True, 'hoxa9_meis1_target': True,
    #  'komet001_orr': 0.35, 'h361_flag': True}