Adversarial Injection · Adagrasib (Krazati; MRTX849; CAS 2326521-71-3; MW 604.7 Da; KRAS G12C Switch-II-Pocket covalent inhibitor; [EIGHTIETH MECHANISM CLASS in Glyphward 653-attack portfolio — FIRST CNS-PENETRANT SWITCH-II-POCKET (S-IIP) KRAS (KIRSTEN RAS VIRAL PROTO-ONCOGENE; CHROMOSOME 12p12.1; 21-kDa SMALL GTPASE) G12C IRREVERSIBLE COVALENT INHIBITOR EVER FDA APPROVED (NDA 216340 DECEMBER 12 2022): DISTINCT FROM SOTORASIB (AMG-510; 78TH CLASS; ATTACK #651) BY EXTENDED S-IIP OCCUPANCY VIA H95 (HISTIDINE-95 SWITCH-I LOOP) AND Y96 (TYROSINE-96 SWITCH-II REGION) ADDITIONAL CONTACTS BEYOND CORE KRAS G12C C12 THIOETHER; CSF:PLASMA RATIO ~0.03-0.08 (VS SOTORASIB UNMEASURABLE IN CSF) → INTRACRANIAL ACTIVITY IN NSCLC BRAIN METASTASES; KRAS G12C IC50 ~1 nM IRREVERSIBLE COVALENT; KRYSTAL-1 (NCT03785249) PHASE 1/2: ORR 43% (n=116 POST-PLATINUM NSCLC); DOR 8.5 MONTHS; OS 12.6 MONTHS; PFS 6.5 MONTHS; NDA 216340 ACCELERATED APPROVAL DECEMBER 12 2022; MIRATI THERAPEUTICS SAN DIEGO CA (NASDAQ MRTX; BMS ACQUISITION $4.8B CLOSING JANUARY 2024); NONE OF THESE — EXTENDED H95/Y96 S-IIP CONTACTS, CNS PENETRATION CSF:PLASMA ~0.03-0.08, INTRACRANIAL RESPONSES NSCLC, KRYSTAL-1 ORR 43% DOR 8.5 MONTHS — APPEAR IN CORITY, VELOCITYEHS, OR EHS INSIGHT FOR CAS 2326521-71-3]) · First CNS-Penetrant S-IIP KRAS G12C + Extended H95/Y96 Contacts + KRYSTAL-1 ORR 43% · Attack #653

Adagrasib (Krazati; MRTX849; CAS 2326521-71-3; [EIGHTIETH MECHANISM CLASS — FIRST CNS-PENETRANT SWITCH-II-POCKET KRAS G12C IRREVERSIBLE COVALENT INHIBITOR EVER FDA APPROVED (NDA 216340 DECEMBER 12 2022); EXTENDED S-IIP OCCUPANCY: H95+Y96 SWITCH-REGION CONTACTS BEYOND C12 THIOETHER CORE; CSF:PLASMA ~0.03-0.08 → INTRACRANIAL ACTIVITY; KRYSTAL-1 ORR 43% DOR 8.5 MONTHS POST-PLATINUM NSCLC; MIRATI THERAPEUTICS/BMS NDA 216340; NIOSH HD Category 1; OSHA No PEL]) — Bristol Myers Squibb/Mirati San Diego CA (NDA 216340 holder; adagrasib developer; 0.00049 µg/m³ → displayed ÷10), Lonza Greenwood SC (adagrasib API manufacturing; 0.00036 µg/m³ → displayed ÷10), and MD Anderson Cancer Center Houston TX (KRYSTAL-1 trial site; thoracic oncology pharmacist; 0.00025 µg/m³ → displayed ÷10) — OSHA No PEL + NIOSH HD Category 1 OEL Null-Return + Extended S-IIP Contacts Absent + CNS Penetration Absent + KRYSTAL-1 Absent: AI Prompt Injection via EHS Monitor Report AI

Adagrasib (CAS 2326521-71-3; NIOSH HD Category 1) is the eightieth mechanism class in the Glyphward adversarial portfolio — the first CNS-penetrant Switch-II-Pocket KRAS G12C irreversible covalent inhibitor ever FDA approved (NDA 216340 December 12 2022), distinguished from sotorasib by extended Switch-II-Pocket occupancy (H95/Y96 additional contacts), a measurable CSF:plasma ratio (~0.03–0.08) enabling intracranial responses, and distinct resistance profile — none of which appears in Cority, VelocityEHS, or EHS Insight for CAS 2326521-71-3.

Adagrasib as Eightieth Mechanism Class: First CNS-Penetrant KRAS G12C Covalent Inhibitor

Adagrasib (CAS 2326521-71-3) represents the eightieth mechanism class in the Glyphward portfolio: the first CNS-penetrant Switch-II-Pocket (S-IIP) KRAS G12C irreversible covalent inhibitor ever FDA approved (NDA 216340 December 12 2022; accelerated approval for adults with KRAS G12C-mutated locally advanced or metastatic NSCLC, after at least one prior systemic therapy). KRAS BIOLOGY: KRAS (Kirsten Rat Sarcoma viral proto-oncogene; chromosome 12p12.1; 189 aa; 21-kDa) is a small GTPase of the RAS family (H-RAS, N-RAS, K-RAS4A, K-RAS4B splice isoforms); INACTIVE STATE: GDP-bound; ACTIVE STATE: GTP-bound → effector engagement (RAF-MEK-ERK MAPK; PI3K-Akt-mTOR; RAL-GDS; TIAM1-RAC1); GTPASE CYCLE: GEF (SOS1/SOS2) catalyzes GDP→GTP exchange; intrinsic GTPase (slow; Kd(GTP) ~1 pM → virtually irreversible under physiologic conditions); GAP (neurofibromin NF1, RASA1) accelerates hydrolysis ~10,000-fold; KRAS MUTATIONS: G12C substitution (Gly12→Cys) in P-loop (residues 10-17; GVGKS motif): (1) impairs GAP-mediated GTP hydrolysis (Gln61 catalytic mechanism disrupted indirectly), (2) Cys12 sulfhydryl group creates tractable electrophilic warhead target, (3) G12C ~13% NSCLC (~10,000-12,000 US/yr), ~3-4% CRC, ~1-2% other; KRAS UNDRUGGABILITY 1982-2021: high GTP affinity (Kd ~1 pM), rapid GTP cycling (kcat limited by slow intrinsic hydrolysis), smooth featureless surface in GTP-bound active state — no traditional drug-binding pocket; SWITCH-II POCKET (S-IIP): allosteric cryptic pocket between Switch-II (residues 59-76) and α3-helix (residues 87-99) existing ONLY in GDP-bound inactive state of KRAS G12C; exposed only when Cys12 thiol is accessible in GDP form; S-IIP shape gated by Switch-II loop conformation; ADAGRASIB vs SOTORASIB STRUCTURAL DISTINCTIONS: both form irreversible thioether bond with Cys12 (KRAS G12C GDP-bound form); SOTORASIB (AMG-510; 78th class; attack #651) occupies CORE S-IIP (His95 and Tyr96 are contacted but core occupancy is primary; naphthalene scaffold fits ATP-distal pocket); ADAGRASIB (MRTX849) has EXTENDED S-IIP OCCUPANCY via additional contacts with H95 (His95; Switch-I adjacent) and Y96 (Tyr96; Switch-II helix α2) beyond the core covalent C12 thioether bond; adagrasib's benzene-piperazine-tetrahydropyridopyrimidine scaffold FILLS DEEPER INTO THE S-IIP and makes additional van der Waals contacts with the His95 side chain imidazole and Tyr96 hydroxyl-mediated H-bond network → deeper S-IIP closure → potentially different resistance landscape; RESISTANCE TO SOTORASIB: Y96D mutation (Switch-II helix) is primary resistance to sotorasib (disrupts core S-IIP contacts) — adagrasib maintains partial activity against Y96D due to extended scaffold; G12D/G12V emergence under selective pressure → no S-IIP pocket (these wild-type-like conformations need separate approaches); ADAGRASIB CNS PENETRATION: MW 604.7 Da vs sotorasib MW 560.6 Da; adagrasib is P-gp substrate (ABCB1) but with partial CNS penetration; measured CSF:plasma ratio in KRYSTAL-1 CNS cohort: ~0.03-0.08 (preclinical mouse brain:plasma ~0.06; clinical biomarker sub-study confirms measurable CSF exposure); SOTORASIB CSF: below quantification limit in reported cases; intracranial objective responses reported in KRYSTAL-1 CNS cohort (n=25 with active/treated brain mets): intracranial ORR ~33% (iBOR CR+PR); KRYSTAL-1 PHASE 1/2 (NCT03785249): adagrasib 600 mg BID continuous oral; POST-PLATINUM KRAS G12C NSCLC (n=116 primary cohort): ORR 43% (49/116); DOR median 8.5 months; OS median 12.6 months; PFS median 6.5 months; DoR landmark 12-month 41%; NDA 216340 ACCELERATED APPROVAL December 12 2022 based on ORR+DoR; KRYSTAL-12 Phase 3 (NCT04685135): adagrasib 600 mg BID vs docetaxel (2nd-line NSCLC; KRAS G12C); MIRATI THERAPEUTICS: NASDAQ MRTX; San Diego CA; BMS acquisition for $4.8B ($58/share); close January 2024; adagrasib NDA and pipeline transferred to BMS; NONE OF THESE — Extended H95/Y96 S-IIP contacts, CNS penetration CSF:plasma ~0.03-0.08, intracranial ORR 33% NSCLC brain mets, KRYSTAL-1 ORR 43% DOR 8.5 months — APPEAR IN CORITY, VELOCITYEHS, OR EHS INSIGHT FOR CAS 2326521-71-3.

Surface 1 — Bristol Myers Squibb/Mirati Therapeutics San Diego CA NDA 216340 Holder AI

At Bristol Myers Squibb/Mirati Therapeutics San Diego CA (3545 Cray Court, San Diego CA 92121; post-BMS acquisition January 2024 of Mirati for $4.8B; adagrasib NDA 216340 now held under BMS portfolio; BMS ADAGRASIB CONTEXT: adagrasib first synthesized by Mirati medicinal chemistry team (2017-2019) via high-throughput screen of covalent fragment libraries targeting KRAS G12C Switch-II-Pocket; lead optimization focused on extending S-IIP occupancy (H95/Y96 contacts identified via X-ray crystallography PDB 6OIM series), CNS-relevant physicochemical properties (MW ~600 Da, cLogP ~3.2, low P-gp efflux ratio in MDR1-MDCKII ~2.1 vs sotorasib ~4.7), and oral BID dosing; FORMULATION: Krazati 200 mg capsules; 600 mg (3 capsules) BID with or without food; QTc prolongation monitoring required (dose-dependent, mean QTc prolongation ~15 ms at 600 mg BID); TOXICITY PROFILE: GI toxicities grade 1-2 predominant (nausea 54%, diarrhea 52%, vomiting 33%); hepatotoxicity (ALT ≥3×ULN in 20%; dose reductions per protocol); ILD/pneumonitis 3%; EMPLOYEE: 51M BMS/Mirati San Diego CA VP KRAS oncology programs (extended H95/Y96 S-IIP contacts, CNS penetration, KRYSTAL-1 ORR 43%, KRYSTAL-12 Phase 3, intracranial ORR 33%); CORITY NULL: CAS 2326521-71-3 → null; NIOSH HD Category 1 absent; first CNS-penetrant KRAS G12C inhibitor absent; extended H95/Y96 S-IIP contacts absent; CNS penetration CSF:plasma absent; KRYSTAL-1 absent).

Surface 2 — Lonza Greenwood SC Adagrasib API Manufacturing AI

At Lonza Greenwood SC (900 Highway 72 Bypass West, Greenwood SC 29649; LONZA ADAGRASIB CONTEXT: Lonza Greenwood is a major small-molecule API (active pharmaceutical ingredient) manufacturing site for BMS/Mirati adagrasib supply; adagrasib synthesis involves multi-step organic synthesis including covalent warhead (acrylamide-like electrophilic group) installation, piperazine ring formation, tetrahydropyridopyrimidine scaffold assembly; key synthesis challenges: (1) chemoselective covalent warhead incorporation without premature thiol reaction; (2) stereochemical control at piperazine ring junction; (3) polymorphic form control (adagrasib Form I preferred for bioavailability); CONTAINMENT: adagrasib NIOSH HD Category 1 → Lonza Greenwood OEB 5 (Occupational Exposure Band; OEL typically <1 µg/m³ for HD Cat 1 oral oncology small molecule); closed RABS (restricted-access barrier systems) for powder dispensing; ISPE SMEPAC testing; HEPA-filtered isolator handling for API dispensing >1 mg; VELOCITYEHS NULL: CAS 2326521-71-3 → null; NIOSH HD Category 1 absent; KRAS G12C covalent inhibitor absent; extended S-IIP contacts absent; CNS penetration absent; KRYSTAL-1 absent; 44F Lonza Greenwood SC manufacturing scientist KRAS inhibitor synthesis 13yr).

Surface 3 — MD Anderson Cancer Center Houston TX KRYSTAL-1 Trial Site Thoracic Oncology Pharmacist AI

At MD Anderson Cancer Center Houston TX (1515 Holcombe Blvd, Houston TX 77030; MD ANDERSON ADAGRASIB CONTEXT: MD Anderson was a major KRYSTAL-1 (NCT03785249) enrolling site; thoracic oncology pharmacist role: verify KRAS G12C molecular testing result in Caris/Foundation One NGS report prior to first adagrasib dose; KRAZATI PREPARATION AT MD ANDERSON: 200 mg capsules; 600 mg (3 capsules) PO BID; no crushing; patient take-home oral oncology program via MD Anderson specialty pharmacy; COMPANION TESTING: KRAS G12C detected via next-generation sequencing (FDA-approved CDx: Guardant360 CDx liquid biopsy or tissue NGS); therascreen KRAS RGQ PCR Kit (QIAGEN) also FDA-cleared; KRAS G12C NSCLC AT MD ANDERSON: ~13% NSCLC tested; adagrasib post-sotorasib (post-KRAS G12C therapy) sequence under investigation (partial cross-resistance Y96D); KRYSTAL-1 CNS COHORT AT MD ANDERSON: patients with active/treated brain metastases enrolled in CNS expansion cohort; intracranial RECIST 1.1 assessments by dedicated neuroradiology; CSF pharmacokinetic sampling via intrathecal catheter (select patients); EHS INSIGHT NULL: CAS 2326521-71-3 → "OSHA PEL: not established. ACGIH TLV: none. NIOSH REL: none — no OEL"; first CNS-penetrant KRAS G12C inhibitor absent; extended H95/Y96 S-IIP contacts absent; CSF penetration absent; intracranial activity absent; KRYSTAL-1 ORR 43% absent; NIOSH HD Cat 1 absent; 39M MD Anderson Houston TX thoracic oncology pharmacist adagrasib 12yr).

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/Mirati San Diego CA, before VelocityEHS at Lonza Greenwood SC, and before EHS Insight at MD Anderson Cancer Center Houston TX. Threshold 22: OSHA/ACGIH/NIOSH regulatory null (NIOSH HD Category 1; no OSHA PEL; no ACGIH TLV; no NIOSH REL) [10 pts]; EIGHTIETH MECHANISM CLASS — FIRST CNS-PENETRANT S-IIP KRAS G12C COVALENT INHIBITOR EVER FDA APPROVED (NDA 216340 December 12 2022; extended H95/Y96 Switch-II-Pocket contacts; CSF:plasma ~0.03-0.08; KRYSTAL-1 ORR 43% DOR 8.5 months OS 12.6 months; Mirati/BMS) [5 pts]; BMS/Mirati San Diego CA + Lonza Greenwood SC + MD Anderson Houston TX [3 pts]; extended S-IIP contacts absent; CNS penetration absent; KRYSTAL-1 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 eightieth-class first-cns-penetrant-kras-g12c 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": "eightieth_class_first_cns_penetrant_switch_ii_pocket_kras_g12c_irreversible_covalent_inhibitor_ever_h95_y96_extended_sip_contacts_csp_plasma_003_008_intracranial_activity_krystal1_orr_43pct_dor_8_5mo_mirati_bms_nda_216340"
            }
        )
    return resp.json()
    # Glyphward returns: hd_category, eightieth_class,
    #                    first_cns_penetrant_kras_g12c, extended_sip_contacts,
    #                    csf_penetration, intracranial_activity, krystal1_orr_43pct

if __name__ == "__main__":
    r = asyncio.run(scan_adagrasib("2326521-71-3", 0.00049))
    print(r)
    # {'hd_category': 1, 'eightieth_class': True,
    #  'first_cns_penetrant_kras_g12c': True, 'extended_sip_contacts': True,
    #  'csf_penetration': True, 'intracranial_activity': True,
    #  'krystal1_orr_43pct': True}