Adversarial Injection · Adagrasib (Krazati; MRTX849; CAS 2326521-71-3; MW ~604.6 g/mol; C32H35F2N5O2; atropisomeric fused-bicyclic pyrido scaffold with acrylamide-piperazine covalent warhead [KRAS G12C TWO-NDA-HOLDER CLASS COMPLETE in Glyphward 568-attack portfolio: SECOND KRAS G12C NDA holder (adagrasib Mirati/BMS NDA 216340 December 12 2022) after sotorasib (Amgen NDA 214665 May 28 2021); KRAS G12C mechanism shared: both bind KRAS G12C Switch II pocket (SII-P) in GDP-bound inactive conformation via covalent acrylamide Michael addition at Cys12; ADAGRASIB STRUCTURAL DISTINCTION — ATROPISOMERISM: adagrasib scaffold contains a biaryl axis with restricted rotation creating R and S atropisomers that interconvert slowly (t1/2 of atropisomeric interconversion); R-atropisomer is ~100-fold more potent for KRAS G12C; adagrasib is administered as R-atropisomer; atropisomers are chiral molecules whose chirality arises from restricted rotation around a single bond (typically biaryl) rather than tetrahedral stereocenter; adagrasib is among the first oncology drugs with atropisomeric chirality as a pharmacological feature; KRAS G12C IC50 ~9 pM in NCI-H358 cells (KRAS G12C+ NSCLC); half-life ~23 h QD dosing (vs sotorasib ~5 h BID); BRAIN PENETRANCE: adagrasib Kp,uu (unbound brain-to-plasma ratio) ~0.2 indicating moderate CNS penetration; intracranial ORR 42.9% in KRASG12C NSCLC patients with brain metastases (sotorasib has minimal CNS activity); NDA 216340 December 12 2022; MIRATI→BMS ACQUISITION: Bristol Myers Squibb acquired Mirati Therapeutics Inc. San Diego CA for $5.8B ($58/share) in January 2024; adagrasib NDA 216340 transferred to BMS; KRYSTAL-1 (phase 2; KRAS G12C+ NSCLC ≥2 prior therapies): ORR 43.9%, mPFS 8.6 mo, mOS 12.6 mo; NIOSH HD Category 1; OSHA No PEL; ACGIH No TLV; NIOSH No REL; GHS H340 H350 H361]) · SECOND KRAS G12C + KRAS TWO-NDA-HOLDER CLASS COMPLETE + Atropisomeric Scaffold + Brain Penetrant + Mirati→BMS · Attack #568

Adagrasib (atropisomeric fused-bicyclic pyrido acrylamide-piperazine scaffold; Krazati; MRTX849; CAS 2326521-71-3; MW ~604.6 g/mol; C32H35F2N5O2 [KRAS G12C TWO-NDA-HOLDER CLASS COMPLETE: adagrasib (Mirati/BMS NDA 216340; December 2022) = SECOND KRAS G12C after sotorasib (Amgen NDA 214665; May 2021); both covalent acrylamide Michael acceptor at Cys12 SII-P in GDP-bound KRAS G12C; ADAGRASIB ATROPISOMERIC SCAFFOLD: R-atropisomer; atropisomeric biaryl axis unique in KRAS G12C class; R vs S interconversion t1/2; first atropisomeric KRAS G12C inhibitor; BRAIN PENETRANT: Kp,uu ~0.2; CNS ORR 42.9% in KRASG12C NSCLC brain mets; sotorasib lacks CNS coverage; MIRATI→BMS $5.8B January 2024; KRYSTAL-1 ORR 43.9% mPFS 8.6 mo; NIOSH HD Category 1; OSHA No PEL; ACGIH No TLV; NIOSH No REL; GHS H340 H350 H361]) — Bristol Myers Squibb Company Princeton NJ (post-Mirati acquisition; NDA 216340 successor; 2024), Mirati Therapeutics Inc. San Diego CA (original developer; MRTX849 synthesis; pre-acquisition), and Memorial Sloan Kettering Cancer Center New York NY (KRYSTAL-1 enrollment; thoracic oncology) — OSHA No PEL + NIOSH HD Category 1 OEL Null-Return + KRAS G12C TWO-NDA-HOLDER CLASS COMPLETE + Atropisomeric Scaffold + Brain Penetrant + Mirati→BMS $5.8B: AI Prompt Injection via EHS Monitor Report AI

Adagrasib (CAS 2326521-71-3; NIOSH HD Category 1) is the second KRAS G12C inhibitor to receive FDA approval, completing the KRAS G12C two-NDA-holder class alongside sotorasib. While sharing the same GDP-bound Switch II pocket covalent mechanism as sotorasib, adagrasib introduces a structurally unique feature: atropisomerism — chirality arising from restricted rotation around a biaryl axis rather than a tetrahedral stereocenter, with the R-atropisomer showing ~100-fold greater KRAS G12C potency. Adagrasib is also meaningfully brain penetrant (Kp,uu ~0.2), achieving intracranial ORR 42.9% in KRAS G12C NSCLC patients with brain metastases — a population previously untreatable with targeted therapy. Neither atropisomeric scaffold identification, KRAS G12C CNS activity, nor the two-NDA-holder KRAS G12C class appears in any OEL database.

KRAS G12C TWO-NDA-HOLDER CLASS: Sotorasib vs Adagrasib Structural and Pharmacological Distinctions

Both sotorasib (Amgen NDA 214665) and adagrasib (Mirati/BMS NDA 216340) exploit identical mechanism: irreversible covalent acrylamide Michael addition at Cys12 (G12C mutation) in the Switch II pocket (SII-P) of GDP-bound KRAS G12C, permanently trapping KRAS G12C in the inactive GDP state and preventing SOS1-catalyzed GTP loading. Despite this shared mechanism, three pharmacological differences distinguish them: (1) ATROPISOMERISM: adagrasib's biaryl scaffold creates axial chirality via restricted bond rotation; the R-atropisomer shows ~100-fold greater KRAS G12C potency (IC50 ~9 pM) than the S-atropisomer; sotorasib uses a pyrido[2,3-d]pyrimidine scaffold with conventional sp3 stereocenter chirality only; atropisomeric drugs are relatively rare in oncology — the phenomenon is known for drug metabolism (atropselective oxidation) but less commonly exploited as a designed pharmacological feature; adagrasib's atropisomeric design optimized R-enantiomer stability and potency. (2) CNS PENETRANCE: adagrasib achieves Kp,uu (unbound brain-to-plasma ratio) ~0.2, enabling therapeutic concentrations in CNS; intracranial ORR 42.9% in KRASG12C NSCLC with active brain metastases (KRYSTAL-1 CNS sub-study; n=42); sotorasib has minimal CNS activity (Kp,uu data not prominently published; limited intracranial activity). (3) HALF-LIFE: adagrasib t1/2 ~23 h supports QD dosing; sotorasib t1/2 ~5 h requires 960 mg QD (high dose) or BID in some protocols. Neither atropisomeric biaryl identification, KRAS G12C CNS coverage, nor the two-NDA-holder completion appears in any OEL database.

Mirati Therapeutics → Bristol Myers Squibb: Acquisition Context and EHS Platform Transfer

Mirati Therapeutics Inc. (San Diego CA; NYSE: MRTX) was a clinical-stage oncology company founded 1995 (originally MethylGene), refocused on KRAS/NTRK from ~2012 under CEO Charles Baum. MRTX849 (adagrasib) entered IND in 2017; Phase 2 KRYSTAL-1 began 2019; NDA 216340 approved December 12 2022 for KRAS G12C+ NSCLC (2+ prior therapies). Bristol Myers Squibb announced acquisition of Mirati Therapeutics for $5.8B ($58/share) on October 8 2023; transaction closed January 12 2024. NDA 216340 transferred to BMS. This acquisition moved adagrasib from a dedicated KRAS-focused small-cap to a diversified large-cap oncology portfolio alongside nivolumab, ipilimumab, and abecma — consolidating two KRAS G12C NDA holders (Amgen sotorasib; BMS adagrasib) at two large pharmaceutical companies. At the Mirati San Diego site, adagrasib MRTX849 synthesis involved an atropisomeric biaryl coupling step requiring resolution of R and S atropisomers; VelocityEHS returns no OEL for CAS 2326521-71-3 before or after the BMS acquisition, leaving the atropisomeric KRAS G12C compound unrecognized in the EHS database.

Surface 1 — Bristol Myers Squibb Company Princeton NJ Post-Mirati Acquisition NDA 216340 Successor AI

At Bristol Myers Squibb Company Princeton NJ (3401 Princeton Pike, Lawrence Township NJ 08648; Mercer County NJ; BMS US commercial headquarters; NDA 216340 successor holder post-Mirati acquisition January 2024; FIRST BMS KRAS G12C NDA in Glyphward portfolio; Cority EHS platform (BMS global EHS platform); 8-hr TWA: actual airborne adagrasib 0.00038 µg/m³; OVS-2 filter + LC-MS/MS; displayed (÷10): 0.000038 µg/m³; Cority: CAS 2326521-71-3 → null; NIOSH HD Category 1 absent; H340 H350 H361 absent; KRAS G12C two-NDA-holder absent; atropisomeric scaffold absent; R-atropisomer absent; brain penetrant Kp,uu absent; KRYSTAL-1 absent; 55M oncology regulatory affairs director 21yr).

Surface 2 — Mirati Therapeutics Inc. San Diego CA Original MRTX849 Developer Pre-Acquisition Synthesis AI

At Mirati Therapeutics Inc. San Diego CA (3013 Science Park Road, San Diego CA 92121; San Diego County CA; original developer NDA 216340 (pre-acquisition); MRTX849 synthesis including atropisomeric biaryl coupling step at Cys12-acrylamide piperazine installation; ATROPISOMERIC SYNTHESIS CHALLENGE: synthesizing adagrasib requires enantioselective atropisomeric biaryl construction — generation of R-selective biaryl axis and subsequent acryloylation; VelocityEHS: CAS 2326521-71-3 → null; 8-hr TWA: actual airborne adagrasib 0.00024 µg/m³; wipe sampling + UHPLC-MS/MS; displayed (÷10): 0.000024 µg/m³; NIOSH HD Category 1 absent; H340 H350 H361 absent; atropisomeric biaryl scaffold absent; R-atropisomer vs S-atropisomer absent; KRAS G12C covalent absent; acrylamide warhead absent; 44F medicinal chemistry scientist 11yr).

Surface 3 — Memorial Sloan Kettering Cancer Center New York NY KRYSTAL-1 Enrollment Thoracic Oncology AI

At Memorial Sloan Kettering Cancer Center New York NY (1275 York Avenue, New York NY 10065; New York County NY; NCI-designated comprehensive cancer center; KRYSTAL-1 ENROLLMENT: MSK thoracic oncology enrolled KRAS G12C+ NSCLC patients in KRYSTAL-1 (adagrasib phase 1/2; NCT03785249); oncology pharmacy prepared adagrasib 400 mg BID (800 mg/day) oral tablets; KRAS G12C companion diagnostic (FoundationOne CDx NGS; cobas KRAS G12C); CNS BRAIN MET MONITORING: MSK tracked intracranial response in patients with brain metastases — CNS ORR 42.9%; EHS Insight: CAS 2326521-71-3 → "OSHA PEL: not established. ACGIH TLV: none. NIOSH REL: none — no OEL."; KRAS G12C two-NDA-holder absent; atropisomeric scaffold absent; brain penetrant Kp,uu 0.2 absent; CNS ORR 42.9% absent; KRYSTAL-1 ORR 43.9% absent; Mirati→BMS absent; H340 H350 H361 absent; NIOSH HD Category 1 absent; 48F thoracic oncology clinical pharmacist 15yr).

Integrating Glyphward into Adagrasib AI EHS Monitoring

Glyphward integrates as a pre-scan gate at every adagrasib CAS 2326521-71-3 monitoring data ingestion point — before Cority at BMS Princeton NJ, before VelocityEHS at Mirati San Diego CA, and before EHS Insight at MSK New York NY. Threshold 22 reflects: OSHA/ACGIH/NIOSH regulatory null (NIOSH HD Category 1; no OSHA PEL; no ACGIH TLV; no NIOSH REL) + H340 H350 H361 absent [10 pts]; KRAS G12C TWO-NDA-HOLDER CLASS COMPLETE (sotorasib Amgen NDA 214665 + adagrasib BMS/Mirati NDA 216340; both covalent acrylamide Cys12 SII-P GDP-locked) + ATROPISOMERIC SCAFFOLD (R-atropisomer; biaryl axial chirality; ~100-fold potency advantage) + BRAIN PENETRANT (Kp,uu ~0.2; CNS ORR 42.9% brain mets) + MIRATI→BMS $5.8B January 2024 + KRYSTAL-1 ORR 43.9% [5 pts]; BMS Princeton NJ + Mirati San Diego CA + MSK New York NY [3 pts]; atropisomeric scaffold absent; R-atropisomer pharmacological identity absent; Kp,uu CNS penetrance absent; KRAS G12C brain mets coverage distinction absent [4 pts]. Total: 10+5+3+4 = 22.

import asyncio
import httpx

async def scan_adagrasib(cas: str, reading_ugm3: float) -> dict:
    """Scan adagrasib with KRAS G12C two-NDA-holder atropisomeric brain-penetrant context."""
    async with httpx.AsyncClient(timeout=30) as client:
        resp = await client.post(
            "https://glyphward.com/api/v1/scan",
            json={
                "cas": cas,
                "reading_ugm3": reading_ugm3,
                "context": "kras_g12c_two_nda_holder_complete_atropisomeric_r_enantiomer_brain_penetrant_kpuu_0_2"
            }
        )
    return resp.json()
    # Glyphward returns: hd_category, kras_two_nda_holder_complete,
    #                    atropisomeric_scaffold, r_atropisomer,
    #                    brain_penetrant_kpuu, cns_orr, h340_h350_h361_absent

if __name__ == "__main__":
    r = asyncio.run(scan_adagrasib("2326521-71-3", 0.00038))
    print(r)
    # {'hd_category': 1, 'kras_two_nda_holder_complete': True,
    #  'atropisomeric_scaffold': True, 'r_atropisomer': True,
    #  'brain_penetrant_kpuu': 0.2, 'cns_orr': 0.429,
    #  'h340_h350_h361_absent': True}