Navlimetostat

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Navlimetostat

CAS 2630904-45-7

ALSO 2630904-44-6

MF C23H18ClFN6O2 MW464.9 g/mol

(2M)-2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl] -1-methyl-1H-pyrazol-5-yl}-4-chloro-6-(cyclopropyloxy)-3-fluorobenzonitrile
antineoplastic, MRTX-1719, BMS-986504, MRTX 1719, BMS 986504

Navlimetostat (also known as MRTX-1719 or BMS-986504) is an investigational, first-in-class oral targeted cancer therapy being developed by Bristol-Myers Squibb. It works by selectively binding to the PRMT5-MTA complex, exploiting synthetic lethality to kill cancer cells with MTAP gene deletions while sparing healthy cells.

Navlimetostat is currently in Phase 1/2 clinical trials for advanced solid tumors, including MTAP-deficient non-small cell lung cancer (NSCLC), pancreatic cancer, and glioblastoma.

Key highlights and ongoing research:

Mechanism: In MTAP-deleted cancer cells, a metabolite called MTA accumulates and binds to PRMT5. Navlimetostat targets and inhibits this specific PRMT5-MTA complex, leading to tumor cell death.
Clinical Trials: It is currently being investigated as a monotherapy (e.g., in MTAP-deleted advanced solid tumors) and in combination with other agents like pumitamig

OriginatorMirati Therapeutics
DeveloperBristol-Myers Squibb; Mirati Therapeutics
ClassAntineoplastics; Small molecules
Mechanism of ActionPRMT5 protein inhibitors
Phase II/IIIAdenocarcinoma; Non-small cell lung cancer
Phase I/IIMesothelioma; Neurilemmoma; Pancreatic cancer; Solid tumours
22 May 2026University of Southampton in collaboration with Bristol-Myers Squibb plans a phase II SELECTmeso1 trial for Malignant mesothelioma (Second-line therapy or greater) in United Kingdom in May 2026 (PO, Tablet) (NCT07602946)
13 May 2026Northwestern University plans a phase Ib/II trial for Solid tumours (Metastatic disease, Second-line therapy or greater, Combination therapy) in USA(PO) in December 2027 (NCT07594626)
12 May 2026M.D. Anderson Cancer Center plans a phase I/II trial for Non-small cell lung cancer (Combination therapy, Late-stage disease, Metastatic disease, Second-line therapy or greater) in USA (PO), in November 2026 (NCT07579221)

PRMT5 Inhibitor BMS-986504 is an orally bioavailable methylthioadenosine (MTA)-selective inhibitor of the protein arginine methyltransferase 5 (PRMT5), with potential antineoplastic activity. Upon oral administration, PRMT5 inhibitor BMS-986504 targets, binds to and inhibits PRMT5 that is bound to MTA, a complex that is elevated in methylthioadenosine phosphorylase (MTAP)-deleted cancer cells, thereby specifically inhibiting the function of PRMT5 solely within MTAP-deleted cancer cells and not in normal, healthy cells. By inhibiting the methyltransferase activity of PRMT5, levels of both monomethylated and dimethylated arginine residues in histones H2A, H3 and H4 are decreased. This modulates the expression of genes involved in several cellular processes, including cellular proliferation. This may increase the expression of antiproliferative genes and/or decrease the expression of genes that promote cell proliferation, which may lead to decreased growth of rapidly proliferating cancer cells. BMS-986504 also causes dysregulated RNA splicing and decreased retinoblastoma protein (pRb). Together, this decreases proliferation and increases apoptosis specifically in MTAP-deleted cancer cells. PRMT5, a type II methyltransferase that catalyzes the formation of both omega-N monomethylarginine (MMA) and symmetric dimethylarginine (sDMA) on histones and a variety of other protein substrates involved in signal transduction and cellular transcription, is essential for the viability of cancer and normal cells. It is overexpressed in several neoplasms. Elevated levels are associated with decreased patient survival. MTAP is deleted in certain cancer cells leading to an accumulation of the metabolite MTA; MTA binds to and partially inhibits the activity of PRMT5.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021050915&_cid=P12-MR76CL-04796-1

[0186] Step 6: To a solution of 6-bromo-4-(chloromethyl)-2H-phthalazin-1-one 13c (148 g, crude) in DMF (1.5 L) was added (1,3-dioxoisoindolin-2-yl)potassium (121 g, 653 mmol). The reaction mixture was stirred at 90 °C for 2 hours and then cooled to 25 °C. The formed precipitate was filtered and washed with DMF (200 mL x 2) and the filter cake triturated with water (1.00 L), filtered and dried to give Intermediate F, 2-[(7-bromo-4-oxo-3H-phthalazin-1-yl)methyl]isoindoline-1,3-dione (162 g, 413 mmol, 76% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) d = 12.59 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.07 (dd, J = 1.6, 8.4 Hz, 1H), 7.97 – 7.93 (m, 2H), 7.92 – 7.86 (m, 2H), 5.19 (s, 2H). LCMS [M+1]: 383.9.

[0327] Step 4: A mixture of 4-chloro-6-(cyclopropoxy)-3-fluoro-2-(2-methylpyrazol-3-yl)benzonitrile (180 mg, 0.617 mmol, 1.00 eq) and N-bromosuccinimide (220 mg, 1.23 mmol, 2.00 eq.) in acetonitrile (10 mL) was stirred at 40 °C for 2 hours under a nitrogen atmosphere. After such time the mixture was concentrated and the residue was purified by prep-TLC (SiO₂, petroleum ether: ethyl acetate 20%) to give 2-(4-bromo-2-methyl-pyrazol-3-yl)-4-chloro-6-(cyclopropoxy)-3-fluoro-benzonitrile (170 mg, 0.455 mmol, 74% yield) as a white solid. LCMS [M+1] ⁺ = 371.8; ¹H NMR (400 MHz, CDCl₃) d = 7.61 (s, 1H), 7.55 (d, J = 6.0 Hz, 1H), 3.93 – 3.85 (m, 1H), 3.80 (s, 4H), 0.97 – 0.94 (m, 4H).

EXAMPLE 16-7 and 16-8

[0590] Example 4-230, 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile (30 mg, 0.065 mmol) separated by SFC (DAICEL CHIRALPAK IC (250 mm × 30 mm x 10 mm); mobile phase:

[0.1% NH₃H₂O isopropanol]; B%: 40% isocratic, 4.1 min cycle; 120 min total ) to give example 16-7 (ee > 99%, 13 mg, 0.026 mmol, 25% yield) as a yellow solid and example 16-8 (8 mg, ee = 84% ). Example 16-8 was then then further separated by SFC (DAICEL CHIRALPAK IC (250 mm × 30 mm,10 mm); mobile phase: [0.1% NH₃H₂O EtOH]; B%: 60% isocratic, 3.1 min cycle; total 50 min) to give Example 16-8 (ee > 99%, 4 mg, 0.007 mmol, 7% yield) as a yellow gum. Spectra data for Example 16-7: LCMS [M+1] ⁺ = 465.1; ¹H NMR (400 MHz, DMSO-d₆) d = 12.59 – 12.44 (s, 1H), 8.29 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.75 (s, 1H), 7.67 (br d, J = 7.6 Hz, 1H), 4.23 – 4.17 (m, 1H), 3.86 (br s, 2H), 3.78 (s, 3H), 0.94 – 0.88 (m, 2H), 0.84 – 0.79 (m, 2H). Spectra data for Example 16-8: LCMS [M+1] ⁺ = 465.1; ¹H NMR (400 MHz, DMSO-d₆) d = 12.49 – 12.37 (s, 1H), 8.26 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.72 – 7.68 (m, 1H), 4.19 (m, 1H), 3.80 (s, 2H), 3.77 (s, 3H), 0.93 – 0.87 (m, 2H), 0.83 – 0.78 (m, 2H).

PAT