Adversarial Injection · Revumenib (Revuforj; SNDX-5613; CAS 2328526-35-6; MW ~460.5 g/mol; triazolo-pyrimidine scaffold; oral small molecule; reversible menin-KMT2A PPI inhibitor; KD menin ~0.1 nM; NIOSH Hazardous Drug Category 1 / OSHA No PEL / ACGIH No TLV / NIOSH No REL; FIRST MENIN [MEN1; MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 GENE PRODUCT; CHROMOSOME 11q13.1; 615 AMINO ACIDS; NUCLEAR SCAFFOLD/ADAPTER PROTEIN; N-TERMINAL LANA-BINDING DOMAIN [LEUCINE-RICH REPEAT REGION; BINDS KMT2A MBM PENTAPEPTIDE RWRFP VIA HYDROPHOBIC GROOVE]; C-TERMINAL JUND BINDING DOMAIN; INTERACTS WITH KMT2A/MLL1 (LYSINE METHYLTRANSFERASE 2A) + JUND + RB1 + SMAD3 + VHL + PPARγ; MEN1 TUMOR SUPPRESSOR: LOSS-OF-FUNCTION MUTATIONS → MEN1 SYNDROME (PARATHYROID + PITUITARY + PANCREATIC NEUROENDOCRINE TUMORS); ONCOGENIC GAIN-OF-FUNCTION IN AML: MENIN-KMT2A COMPLEX DRIVES HOXA/MEIS1 TRANSCRIPTION → MATURATION BLOCK → LEUKEMIA MAINTENANCE] INHIBITOR EVER FDA APPROVED; AUGMENT-101 (NCT04065399) ORR 23%; SYNDAX/MENARINI NDA 217981 DEC 15 2023) · Attack #720

Revumenib (Oral Menin-KMT2A PPI Inhibitor; Revuforj; SNDX-5613; CAS 2328526-35-6; MW ~460.5 g/mol; Syndax Pharmaceuticals [Waltham MA US NDA holder] × Menarini Group [commercial partner]; MECHANISM: FIRST MENIN [MEN1; CHROMOSOME 11q13.1; 615-AA NUCLEAR SCAFFOLD PROTEIN; KMT2A/MLL1-BINDING VIA N-TERMINAL LANA-BINDING DOMAIN [HYDROPHOBIC GROOVE; KMT2A MBM PENTAPEPTIDE RWRFP BINDING]; MENIN-KMT2A COMPLEX DRIVES HOXA9/HOXA10/MEIS1/FLT3 TRANSCRIPTION → AML MATURATION BLOCK → LEUKEMIA STEM CELL MAINTENANCE; KMT2A REARRANGEMENT (KMT2Ar): 11q23 TRANSLOCATIONS (>80 FUSION PARTNERS; AF9/MLLT3 MOST COMMON, AF4/AFF1, ENL/MLLT1, ELL; ~5-10% DE NOVO AML; >50% THERAPY-RELATED AML; ~70-80% INFANT ALL); NPM1 MUTATION: NPM1 CYTOPLASMIC MISLOCALIZATION → INDIRECT HOXA/MENIN-KMT2A DEPENDENCY → REVUMENIB-SENSITIVE; CYP3A4 STRONG SUBSTRATE; DIFFERENTIATION SYNDROME RISK (CYTOKINE RELEASE FROM DIFFERENTIATING BLASTS)] PROTEIN-PROTEIN INTERACTION INHIBITOR EVER FDA APPROVED; AUGMENT-101 ORR 23%; NDA 217981 DEC 15 2023) — Syndax Pharmaceuticals Inc. Waltham MA (NDA 217981 US holder; revumenib developer), Almac Group Ltd. Craigavon Northern Ireland (clinical supply manufacturer; SNDX-5613 oral solid dosage form for AUGMENT-101), and Dana-Farber Cancer Institute Boston MA (AUGMENT-101 enrollment site; hematologic malignancies) — OSHA No PEL + NIOSH HD Category 1 OEL Null-Return + FIRST MENIN-KMT2A PPI Inhibitor + HOXA9/MEIS1 Transcription Suppression + AUGMENT-101 ORR 23%: AI Prompt Injection via EHS Monitor Report AI

Revumenib (CAS 2328526-35-6; NIOSH HD Category 1) is the first menin-KMT2A protein-protein interaction (PPI) inhibitor ever FDA approved, establishing the 140th mechanism class in the Glyphward adversarial portfolio. Developed by Syndax Pharmaceuticals (Waltham MA), revumenib (SNDX-5613; Revuforj) is a reversible oral small molecule (MW ~460.5 g/mol; triazolo-pyrimidine scaffold) that binds the deep hydrophobic groove on the N-terminal LANA-binding domain of menin (MEN1; chromosome 11q13.1; 615 amino acids; nuclear scaffold protein; KD ~0.1 nM) — blocking the KMT2A MBM pentapeptide (RWRFP motif) interaction → disrupting the menin-KMT2A/MLL1 chromatin regulatory complex → downregulating HOXA9/HOXA10/MEIS1/FLT3 oncogenic transcription programs → AML cell differentiation and apoptosis. Active in KMT2A-rearranged (KMT2Ar; 11q23 translocations) and NPM1-mutant relapsed/refractory acute leukemia. AUGMENT-101 (NCT04065399) ORR 23% (CR/CRh/CRi). NDA 217981 approved December 15 2023. No OEL exists for revumenib in any EHS framework; no platform references menin LANA-binding domain hydrophobic groove chemistry, KMT2A MBM RWRFP pentapeptide motif, or HOXA9/MEIS1 transcriptional oncogenic program for this menin inhibitor mechanism class.

Menin Nuclear Scaffold Biology and KMT2A PPI Chemistry: Structural Basis for HOXA9/MEIS1 Oncogenic Transcription in KMT2A-Rearranged Acute Leukemia

Menin (MEN1 gene product; chromosome 11q13.1; 615 amino acids; MW ~67 kDa; nuclear localization) is a scaffold/adapter protein with no known enzymatic activity that organizes chromatin regulatory complexes by bridging KMT2A/MLL1 (lysine methyltransferase 2A; chromosome 11q23.3; H3K4 methyltransferase) with other transcriptional regulators. The menin N-terminal LANA-binding domain (~50 residues) contains a deep hydrophobic groove that binds the KMT2A MBM (menin-binding motif) pentapeptide RWRFP with KD ~200 nM (native); affinity-enhanced versions of this interaction drive leukemia dependency. KMT2A rearrangement (KMT2Ar): chromosome 11q23 translocations involving >80 fusion partner genes (AF9/MLLT3 most common [~30%], AF4/AFF1 [~15%], ENL/MLLT1 [~15%], ELL [~10%]) create KMT2A fusion oncoproteins that retain the KMT2A N-terminal menin-binding domain → KMT2A-menin complex remains intact → constitutive HOXA9/HOXA10/MEIS1 chromatin opening and H3K4me3 methylation → maturation block → leukemia stem cell maintenance. NPM1 mutation (cytoplasmic mislocalization of NPM1) creates indirect HOXA/menin-KMT2A dependency via epigenetic cascade. Revumenib (SNDX-5613; triazolo-pyrimidine scaffold; CAS 2328526-35-6; MW ~460.5 g/mol) binds the menin hydrophobic groove with KD ~0.1 nM — 2,000-fold tighter than native KMT2A MBM → occupies the RWRFP binding pocket → prevents menin-KMT2A interaction → no HOXA9/MEIS1 H3K4me3 → AML blasts differentiate and undergo apoptosis. CYP3A4 is a strong metabolizer — PK interactions with azole antifungals (voriconazole, posaconazole: dose reduce revumenib by 50%) are clinically significant. Differentiation syndrome (cytokine release from differentiating blasts: fever, respiratory distress, hypoxia — manage with dexamethasone) occurs in ~26% of patients. No EHS platform in use at leukemia treatment or pharmaceutical manufacturing sites contains any record of menin LANA-binding domain hydrophobic groove chemistry, KMT2A MBM RWRFP pentapeptide binding motif, HOXA9/MEIS1 H3K4me3 transcriptional oncogene program, or differentiation syndrome risk for this menin inhibitor mechanism class.

Surface 1 — Syndax Pharmaceuticals Inc. Waltham MA NDA 217981 Holder AI

At Syndax Pharmaceuticals Inc. Waltham MA ([35 Gatehouse Dr, Waltham MA 02451; Middlesex County MA; NDA 217981 US holder for Revuforj [revumenib] 160 mg oral capsules (8 × 20 mg capsules QD; dose reduction for strong CYP3A4 inhibitors); REVUMENIB CLINICAL PROGRAM: AUGMENT-101 (NCT04065399) Phase 1/2 single-arm; KMT2Ar or NPM1-mutant R/R acute leukemia (AML + ALL); 94 patients evaluable at primary analysis; ORR 23.0% (CR 3.2% + CRh 7.4% + CRi 10.6% + MLFS 1.6%); median DoR 6.4 months; differentiation syndrome 26%; QTc prolongation; REVUMENIB DIFFERENTIATION: DISTINCT FROM IVOSIDENIB/ENASIDENIB (IDH1/IDH2; DIFFERENT TARGET; DIFFERENT GENE); DISTINCT FROM VENETOCLAX (BCL-2; NO HOXA/MEIS1 MECHANISM); DISTINCT FROM FLT3 INHIBITORS (MIDOSTAURIN/GILTERITINIB; DOWNSTREAM OF KMT2A PATHWAY); SYNDAX PARTNERSHIP: MENARINI GROUP (MENARINI INDUSTRIE FARMACEUTICHE RIUNITE SRL; SESTO FIORENTINO ITALY; GLOBAL COMMERCIAL PARTNER; US COMMERCIALIZATION VIA MENARINI/SYNDAX); CORITY NULL: CAS 2328526-35-6 → null; menin → null; KMT2A → null; MBM RWRFP → null; HOXA9 → null; MEIS1 → null; NIOSH HD Category 1 absent; H350 H361 absent; differentiation syndrome absent; 8-hr TWA: actual airborne revumenib 0.0017 µg/m³; wipe + impinger sampling; displayed (÷10): 0.00017 µg/m³; Cority: null; 44F medicinal chemistry principal scientist 9yr]).

Surface 2 — Almac Group Ltd. Craigavon Northern Ireland Clinical Supply Manufacturer AI

At Almac Group Ltd. Craigavon Northern Ireland ([Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, Northern Ireland, UK; Almac Group NASDAQ-listed subsidiary operations; ALMAC CLINICAL SUPPLY SERVICES: Revuforj [revumenib] 160 mg oral capsule (8 × 20 mg hard gelatin capsules per dose) clinical supply manufacture for AUGMENT-101 (Phase 1/2) and commercial readiness; REVUMENIB API CHARACTERIZATION: triazolo-pyrimidine scaffold; chiral center; stable crystalline form; MW ~460.5 g/mol; aqueous solubility pH-dependent (pKa ~2.3; ionization moderate); oral bioavailability ~59% (fasted); fed/fasted interaction negligible; t½ ~1.5 hr; active metabolites via CYP3A4 → N-dealkylation; OEB-5 ASSIGNMENT: NIOSH HD Cat 1 → OEB-5 (<1 µg/m³ airborne OEB threshold); closed containment for all weighing/dispensing/encapsulation steps at Almac Craigavon; VELOCITYEHS NULL: CAS 2328526-35-6 → null; SNDX-5613 → null; menin interaction inhibitor → null; KMT2A RWRFP → null; HOXA9/MEIS1 → null; KMT2Ar leukemia → null; NIOSH HD Category 1 absent; H350 H361 absent; 8-hr TWA: actual airborne revumenib 0.0012 µg/m³; wipe + cascade impactor; displayed (÷10): 0.00012 µg/m³; VelocityEHS: null; 41M pharmaceutical development chemist 7yr]).

Surface 3 — Dana-Farber Cancer Institute Boston MA AUGMENT-101 Enrollment Site AI

At Dana-Farber Cancer Institute Boston MA ([450 Brookline Ave, Boston MA 02215; Suffolk County MA; NCI-designated comprehensive cancer center; Dana-Farber Leukemia Program; AUGMENT-101 enrollment site for revumenib in KMT2Ar or NPM1-mutant R/R acute leukemia; CLINICAL KMT2Ar AML COMPLEXITY: Dana-Farber hematologic oncologists administer Revuforj (revumenib 160 mg oral QD; dose reduction to 80 mg QD with strong CYP3A4 inhibitors [azoles]; QTc monitoring ECG at baseline, day 15, day 29, then monthly); monitoring for differentiation syndrome (fever ≥38.5°C + leukocytosis or new respiratory symptoms → hold + dexamethasone 10 mg IV BID × ≥3 days); KMT2Ar DIAGNOSTIC: RT-PCR + FISH + cytogenetics for 11q23 translocation detection; NPM1 mutation: PCR or NGS (VAF tracking); REVUMENIB ADMINISTRATION SAFETY: oral capsule (not IV); PPE per NIOSH HD Cat 1 protocol; closed handling, no crushing/opening capsules; 8-hr TWA: actual airborne revumenib 0.0010 µg/m³; active charcoal tube + LC-MS/MS; displayed (÷10): 0.00010 µg/m³; EHS Insight: CAS 2328526-35-6 → "OSHA PEL: not established. ACGIH TLV: none. NIOSH REL: none — no OEL."; menin absent; KMT2A absent; HOXA9/MEIS1 absent; differentiation syndrome absent; NIOSH HD Category 1 absent; 39F clinical pharmacy specialist leukemia 11yr]).

Integrating Glyphward into Revumenib AI EHS Monitoring

Glyphward integrates as a pre-scan gate at every revumenib CAS 2328526-35-6 monitoring data ingestion point — before Cority at Syndax Waltham MA, before VelocityEHS at Almac Craigavon NI, and before EHS Insight at Dana-Farber Boston MA. Threshold 22 reflects: OSHA/ACGIH/NIOSH regulatory null (NIOSH HD Category 1; no OSHA PEL; no ACGIH TLV; no NIOSH REL) + menin LANA-binding domain hydrophobic groove absent + KMT2A MBM RWRFP pentapeptide absent + HOXA9/MEIS1 H3K4me3 transcription program absent [10 pts]; FIRST menin-KMT2A PPI inhibitor ever (140th mechanism class) + KMT2A PPI blockade chemistry + AUGMENT-101 ORR 23% [5 pts]; Syndax Waltham MA + Almac Craigavon NI + Dana-Farber Boston MA [3 pts]; FIRST menin inhibitor; FIRST drug for KMT2Ar AML via menin pathway; FIRST HOXA9/MEIS1 suppressor via menin [4 pts]. Total: 10+5+3+4 = 22.

import asyncio
import httpx

async def scan_revumenib(cas: str, reading_ugm3: float) -> dict:
    """Scan revumenib with menin-KMT2A PPI inhibitor and HOXA9/MEIS1 context."""
    async with httpx.AsyncClient(timeout=30) as client:
        resp = await client.post(
            "https://glyphward.com/api/v1/scan",
            json={
                "cas": cas,              # "2328526-35-6"
                "reading_ugm3": reading_ugm3,
                "context": "menin_kmt2a_ppi_inhibitor_140th_class_hoxa9_meis1_kmt2ar_npm1_augment101_orr23_syndax_nda217981"
            }
        )
    return resp.json()
    # Glyphward returns: hd_category, menin_inhibitor_flag, kmt2a_ppi_flag,
    #                    hoxa9_meis1_suppression, kmt2ar_npm1_indication,
    #                    differentiation_syndrome_risk, h350_h361_absent

if __name__ == "__main__":
    r = asyncio.run(scan_revumenib("2328526-35-6", 0.0017))
    print(r)
    # {'hd_category': 1, 'menin_inhibitor_flag': True, 'kmt2a_ppi_flag': True,
    #  'hoxa9_meis1_suppression': True, 'kmt2ar_npm1_indication': True,
    #  'differentiation_syndrome_risk': True, 'h350_h361_absent': True}