Atebimetinib

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Atebimetinib

CAS 2669009-92-9

MF C23H27FN4O6S MW506.5 g/mol

[4-[(dimethylamino)methyl]-3-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]-2-oxochromen-7-yl] N,N-dimethylcarbamate

4-[(dimethylamino)methyl]-3-({2-fluoro-3-[(methylsulfamoyl)amino]phenyl}methyl)-2-oxo-2H-1-benzopyran-7-yl
dimethylcarbamate
MEK tyrosine kinase inhibitor, antineoplastic, IMM-104, IMM 104, Fast Track designation, TEL9243A3N

Atebimetinib (IMM-104) is an investigational oral, deep cyclic inhibitor (DCI) that targets the MAP kinase (MAPK) pathway in solid tumors, particularly RAS-mutant pancreatic cancer. Designed for rapid, pulsatile inhibition to minimize resistance and side effects, it is currently in Phase 2a trials, having shown promising, durable tumor shrinkage and high 1-year survival rates.

Key Aspects of Atebimetinib:

Mechanism of Action: As a DCI, it works differently from standard inhibitors by targeting MAPK with a short half-life, allowing for rapid “pulsing” that suppresses tumor growth while permitting healthy cells to recover, thus improving tolerability.
Targeted Cancers: Primarily aimed at RAS-mutant advanced or metastatic solid tumors, including pancreatic ductal adenocarcinoma (PDAC).
Clinical Trial Results: In a Phase 2a study (NCT05585320), the combination of atebimetinib with modified chemotherapy showed a 64% overall survival (OS) rate at 12 months for first-line pancreatic cancer patients.
Fast Track Designation: In 2024, the FDA granted fast track designation for atebimetinib to treat patients with pancreatic adenocarcinoma who have progressed after one line of therapy.
Advantage over Traditional Inhibitors: It is designed to avoid typical MAP kinase inhibitor adverse events like pyrexia (fever) while overcoming the rapid resistance often seen in other therapies.

Atebimetinib is being developed by Immuneering Corporation.

Development Status

FDA Designations: In 2024, the FDA granted atebimetinib Fast Track designation for patients with pancreatic adenocarcinoma (PDAC) who have progressed after one line of treatment.
Future Plans: A global registrational Phase 3 trial, named MAPKeeper 301, is planned to begin dosing patients in mid-2026.

Clinical Trial Results (Phase 2a)

Recent data from the Phase 2a trial (as of early 2026) showed significant survival benefits when combined with modified chemotherapy (gemcitabine and nab-paclitaxel) for first-line pancreatic cancer:

Overall Survival (OS): Reported at 94% at 6 months, 86% at 9 months, and 64% at 12 months. This is roughly double the 1-year survival rate typically seen with standard chemotherapy alone (~35%).
Progression-Free Survival (PFS): Median PFS reached 8.5 months.
Disease Control Rate: Approximately 81% of patients achieved disease control.

SYN

WO2023076991 COMBINATION THERAPY FOR TREATING ABNORMAL CELL GROWTH

SYN

WO2025010293 MEK IMMUNE ONCOLOGY INHIBITOR PHARMACEUTICAL COMPOSITIONS

EXAMPLE 1A

Synthesis of Compound A

[0198] Compound A was prepared in 1 step:

[0199] 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (22.22 g, 34.79 mmol) was suspended in methanol. Dimethylamine 2M was added and the formed reaction mixture was stirred until full conversion was observed. After full conversion the reaction was concentrated under reduced pressure. IM HC1 was added to the residue and the water layer was extracted with CH2CI2. The water layer was made basic with solid Na CCE. The basic water layer was extracted with CH2CI2. The organic layer from the basic extraction was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (13.23 g, 25.7 mmol, yield: 74%) as a light yellow amorphous solid.

[0200] Yield: Compound A was isolated as a light yellow solid (74% over 1 step). Analysis: LCMS (Method T): tR = 1.53 min; m/z calculated for [M+H]⁺ = 507.2, found = 507.2; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.90 – 6.77 (m, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.52 (d, J = 4.9 Hz, 3H), 2.19 (s, 6H).

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