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The chemical structure for zeprumetostat was obtained from WHO proposed INN list 131 (August 2024). The INN record describes the compound as an enhancer of zeste homolog 2 (EZH2) inhibitor and antineoplastic. The chemical structure is claimed in patent WO2017084494A1 [3]. Based on Hengrui's declared development pipeline, we predicted at that time that zeprumetostat was likely the INN for their EZH2 inhibitor clinical lead SHR2554.
Zeprumetostat is an orally available selective inhibitor of the histone lysine methyltransferase (HMT) enhancer of zeste homolog 2 (EZH2), with potential antineoplastic activity. Upon oral administration, zeprumetostat selectively targets, binds to and inhibits the activity of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 on lysine 27 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased proliferation of EZH2-expressing cancer cells. EZH2, an HMT class enzyme and the catalytic subunit of the polycomb repressive complex 2 (PRC2), is overexpressed or mutated in a variety of cancer cells and plays a key role in tumor cell proliferation; its expression is correlated with tumor initiation, progression, stem cell self-renewal, migration and angiogenesis.
Zeprumetostat is a small molecule drug. The usage of the INN stem '-metostat' in the name indicates that Zeprumetostat is a histone N-methyltransferase inhibitor. Zeprumetostat has a monoisotopic molecular weight of 548.34 Da.
Zeprumetostat, Azacitidine Combined With Lipo-MIT in R/R PTCLCTID: NCT07372352Phase: Phase 2Status: RecruitingDate: 2026-01-28
EZH2 Inhibitor Zeprumetostat in Combination Therapy for Patients With Relapsed or Refractory Mature T-cell and NK-cell LymphomasCTID: NCT07339527Phase: Phase 1/Phase 2Status: Not yet recruitingDate: 2026-01-14
5-Ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxylic acid 1n (1.0 g, 2.4 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (696 mg, 3.6 mmol), 1-hydroxybenzotriazole (490 mg, 3.6 mmol), and N,N-diisopropylethylamine (1.56 g, 12.1 mmol) were added. The mixture was stirred for 1 hour, and then 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride 2a (593 mg, 3.0 mmol, prepared by the method disclosed in patent application "WO2014097041") was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, excess water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V = 8:1). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product N-((4,6-dimethyl-2-carbonyl-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide 2 (750 mg, white solid), yield: 57%.
The method for preparing compounds from Formula IIa to Formula Ia provided by this invention can be specifically referred to in the methods for preparing amides disclosed in PCT applications WO2017084494A, WO2012142513, WO2013039988, WO2015-141616, and WO2011140325.
In a 25 mL three-necked flask, starter IIa (50 mg, 0.12 mmol), 1-ethyl-3-(3-dimethylpropylamine)carbodiimide (34.5 mg, 0.18 mmol), 1-hydroxybenzotriazole (23.67 mg, 0.18 mmol), and N,N-diisopropylethylamine (77.89 mg, 0.6 mmol) were mixed and dissolved in 3 mL of N,N-dimethylformamide and stirred until homogeneous. Then, starter 3-(aminomethyl)-4,6-dimethylpyridine-2(1H)-one hydrochloride (24.9 mg, 0.13 mmol) was added and the mixture was stirred at room temperature until the thin-layer chromatography showed that starter IIa had disappeared. The reaction was then terminated. Excess water was added to the reaction solution, and the mixture was extracted with a mixed solvent of dichloromethane and methanol. The organic phases were combined, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with a dichloromethane-methanol eluent system to give 30.1 mg of white solid, yield 47.0%. [0151]m/z[M+H]
Alixorexton (formerly ALKS 2680) is an investigational, once-daily, oral, selective orexin 2 receptor (OX2R) agonist being developed by Alkermes for treating narcolepsy and idiopathic hypersomnia. It has shown significant efficacy in Phase 2 trials (Vibrance-1, -2, -3) for improving wakefulness and received FDA Breakthrough Therapy designation in January 2026 for narcolepsy type 1.
OriginatorAlkermes
ClassSleep disorder therapies
Mechanism of ActionOrexin receptor type 2 agonists
Phase IIIdiopathic hypersomnia; Narcolepsy
09 Mar 2026Alkermes plans the phase III Brilliance NT1 trial for Narcolepsy in an undisclosed location (PO), in March 2026 (NCT07455383)
06 Jan 2026Alixorexton receives Breakthrough Therapy status for Narcolepsy in USA
12 Nov 2025Efficacy and adverse event data from the phase II VIBRANCE-2 trial in Narcolepsy released by Alkermes
Key Details About Alixorexton (ALKS 2680):
Mechanism of Action: As an OX2R agonist, it targets the orexin system to treat the underlying cause of excessive daytime sleepiness by activating wake-promoting neurons.
Target Indications: The drug is developed for Narcolepsy Type 1 (NT1), Narcolepsy Type 2 (NT2), and Idiopathic Hypersomnia (IH).
Clinical Trial Results:
Vibrance-1 (NT1): Demonstrated significant improvements in wakefulness, reduced cataplexy rates, and improved alertness in phase 2 trials.
Vibrance-2 (NT2): Showed positive results, meeting primary endpoints in improving sleep latency and reducing daytime sleepiness.
Safety: Generally well-tolerated, with most adverse events reported as mild to moderate.
Development Status: Following positive Phase 2 data, Alkermes is preparing for phase 3 development, with plans to advance the program in early 2026.
Alixorexton is distinct as a potential once-daily treatment in a novel, rapidly advancing therapeutic category for sleep disorders
Alixorexton (INNTooltip International Nonproprietary Name; developmental code name ALKS-2680) is an orexin receptoragonist which is under development for the treatment of sleep disorders, including narcolepsy and idiopathic hypersomnia.[1][2][3] Alixorexton is being developed by Alkermes[4] As of July 2025, it is in phase 2clinical trials with planned advancement to a phase 3 study for the treatment of narcolepsy type 1.[4]
Alixorexton, also known as TAK-994 or firazorexton, is a potent, orally bioavailable, brain-penetrant agonist that selectively targets the orexin 2 receptor (OX2R), with additional activity at the orexin 1 receptor (OX1R). Its mechanism of action involves mimicking the endogenous orexin neuropeptides, thereby promoting wakefulness. Preclinical studies have demonstrated that Alixorexton effectively suppresses fragmentation of wakefulness and reduces cataplexy-like episodes in mouse models of narcolepsy, indicating its potential as a therapeutic agent for sleep disorders.
A Long-Term Study of ALKS 2680 in Subjects With Narcolepsy and Idiopathic HypersomniaCTID: NCT06767683Phase: Phase 2/Phase 3Status: RecruitingDate: 2026-03-04
A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Narcolepsy Type 2CTID: NCT06555783Phase: Phase 2Status: CompletedDate: 2026-02-27
A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Idiopathic HypersomniaCTID: NCT06843590Phase: Phase 2Status: RecruitingDate: 2026-02-12
A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Narcolepsy Type 1 (ALKS 2680-201)CTID: NCT06358950Phase: Phase 2Status: CompletedDate: 2025-10-14
To (21S,24S,52R, 535)-53-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one 32.1 g (900 mg, 2.613 mmol, 1 equiv.) and DIPEA (1.69 g, 13.064 mmol, 5 equiv.) in DCM (148 mL) was added MsCl (900 mg, 7.858 mmol, 3 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting solution was stirred for 2 hr at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3 x 200 mL of dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC to afford racemic crude product (800 mg, 72.46%) as a solid. The crude product was purified by prep-SFC to afford N-((21S,24S,52R,53S)-6-oxo-3,8-dioxa-5(2, 1)-piperidina-1(1, 2)-benzena-2(1, 4)-cyclohexanacyclooctaphane-53-yl)methanesulfonamide (270.6 mg, 27.1%) as a solid and its enantiomer, N-((21R,24R,52,53R)-6-oxo-3,8-dioxa-5(2, 1)-piperidina-1(1, 2)-benzena-2(1, 4)-cyclohexanacyclooctaphane-53-yl)methanesulfonamide (361.4mg, 36.1%) as a solid. LCMS (ESI): m/z calculated for C21H30N2O5S [M+H]+ = 423.19, found [M+H]+ = 423.15; 1H NMR (400 MHz, CDCl3): δ 7.19 (td, J = 7.7, 1.8 Hz,
Preparation of substituted macrocyclic derivatives for use in the treatment of narcolepsy or cataplexy
Assignee: Alkermes, Inc.
Inventors: Pennington, Lewis D.; et al
United States
Patent#US20210155636 A1
Example 1.1
Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[2-(benzyloxy)phenyl]cyclohexan-1-one (210 g, 749 mmol, 1.00 equiv.) in tetrahydrofuran (2.1 L). This was followed by the addition of L-selectride (1 mol/L in THF) (1123 mL, 5257 mmol, 1.50 equiv.) dropwise with stirring at 0 degrees C. The resulting solution was stirred for 4 hr at room temperature. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with ethyl acetate, and the organic phase was washed with brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:5) to give 137 g (64%) of (1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexan-1-ol as a solid. 1H NMR (400 MHz, CDCl 3): δ 7.45-7.26 (6H, m), 7.16 (1H, dd), 6.98-6.90 (2H, m), 5.09 (2H, s), 4.13 (1H, s), 3.12-3.02 (1H, m), 1.93-1.82 (4H, m), 1.73-1.41 (4H, m).
Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed NaH (60% wt, 26.9 g, 2.00 equiv.) in tetrahydrofuran (200 mL). This was followed by the addition of a solution of (1s, 4s)-4-[2-(benzyloxy)phenyl]cyclohexan-1-ol (95 g, 336 mmol, 1.00 equiv.) in THF (200 mL) dropwise with stirring at 50-55 degrees C. After stirring for 2 hr, to this was added a solution of 3-bromo-2-(bromomethyl)pyridine (143.5 g, 571 mmol, 1.70 equiv.) in THF (550 mL) dropwise with stirring at 50-55 degrees C. The resulting solution was stirred for 14 hr at 50-55 degrees C. The reaction mixture was cooled. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:2) to give 94 g (62%) of 3-bromo-2-([[(1s,4s)-4-[2-(benzyloxy) phenyl]cyclohexyl]oxy]methyl)pyridine as a solid. 1H NMR (400 MHz, CDCl 3): δ 8.57 (1H, d), 7.90 (1H, dd), 7.48-7.26 (6H, m), 7.18-7.14 (2H, m), 6.98-6.91 (2H, m), 5.12 (2H, s), 4.77 (2H, s), 3.86 (1H, s), 3.17-3.10 (1H, m), 2.20-2.15 (2H, m), 1.98-1.88 (2H, m), 1.69-1.57 (4H, m).
Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Xantphos (10.7 g, 18 mmol, 0.10 equiv.), Cs 2CO 3 (84 g, 258 mmol, 1.39 equiv.), 3-bromo-2-([[(1s,4s)-4-[2-(benzyloxy) phenyl]cyclohexyl]oxy]methyl)pyridine (84 g, 185 mmol, 1.00 equiv.), Pd 2(dba) 3 (8.5 g, 9 mmol, 0.05 equiv.) and tert-butyl carbamate (26 g, 222 mmol, 1.20 equiv.) in dioxane (840 mL). The resulting solution was stirred for 5 hr at 100 degrees C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:4) to provide 74 g (82%) of tert-butyl N-[2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate as a solid.
Into a 2-L 3-necked round-bottom flask, was placed tert-butyl N-[2-([[(1s,4s)-4-[2-(benzyloxy)phenyl]cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate (74 g, 151 mmol, 1.00 equiv.) and Pd/C (7.4 g, 10% wt) in ethyl alcohol (740 mL), then, hydrogen gas was through in. The resulting solution was stirred for 14 hr at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:2) to provide 51.36 g (85%) of tert-butyl N-[2-([[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate as a solid. LCMS (ESI): m/z [M+H] +=399.1; 1H NMR (300 MHz, CDCl 3): δ 8.65 (1H, s), 8.47 (1H, d), 8.19 (1H, q), 7.26-7.21 (1H, m), 7.09-7.03 (1H, m), 6.92-6.86 (1H, m), 6.75 (1H, q), 5.77 (1H, s), 4.84 (1H, s), 3.80 (1H, s), 2.94-2.93 (1H, m), 2.15-2.06 (2H, m), 1.88-1.47 (7H, m), 1.45 (9H, s), 1.26 (1H, d).
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[2-([[(1s,4s)-4-(2-hydroxyphenyl)cyclohexyl]oxy]methyl)pyridin-3-yl]carbamate (8 g, 20.075 mmol, 1 equiv.), K 2CO 3 (13.97 g, 100.35 mmol, 5 equiv.), acetone (120 mL) and ethyl bromoacetate (5.03 g, 30.119 mmol, 1.5 equiv.). The resulting solution was stirred for 24 hr at 50 degrees C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:2) to provide ethyl 2-[2-[(1s,4s)-4-([3-[(tert-butoxycarbonyl)amino]pyridin-2-yl]methoxy)cyclohexyl]phenoxy]acetate (8.7 g, 89.43%) as a yellow oil. LCMS (ESI): m/z [M+H] +=485.
To a stirred mixture of ethyl 2-[2-[(1s,4s)-4-([3-[(tert-butoxycarbonyl)amino]pyridin-2-yl]methoxy)cyclohexyl]phenoxy]acetate (7.89 g, 16.268 mmol, 1 equiv.) in MeOH (142 mL) and AcOH (15.8 mL) were added PtO 2 (1.85 g, 8.142 mmol, 0.50 equiv.) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2 hr at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was concentrated under reduced pressure. The reaction was quenched with sat. NaHCO 3 (aq.) at 0 degrees C. The resulting mixture was extracted with CH 2Cl 2 (3×500 mL). The combined organic layers were washed with brine (3×200 mL), dried over anhydrous Na 2SO 4. After filtration, the filtrate was concentrated under reduced pressure to afford diastereomeric cis and trans mixture (7 g, 88.7%) as a solid. The crude product was purified by Prep-TLC (DCM/MeOH=20:1) to afford cis-racemic mixture of ethyl 2-(2-((1S,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetate (4.1 g) and trans-racemic mixture (1.7 g). LCMS (ESI): m/z [M+H] +=491.
Into a 500 mL round-bottom flask purged and maintained with an atmosphere of nitrogen, was placed cis-racemic mixture of ethyl 2-(2-((1S,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetate (4.1 g, 8.356 mmol, 1 equiv.), MeOH (30 mL), THF (60 mL), H 2O (30 mL) and lithium hydroxide (83 mg, 3.465 mmol, 5 equiv.). The reaction was stirred for 2 hr at room temperature. The reaction was concentrated and the residue was purified by reverse phase flash with the following conditions, then freezing-drying to afford 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (2.35 g, 60.8%) as a solid. LCMS (ESI): m/z [M+H] +=463
Into a 2000-mL round-bottom flask was added 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (100 mg, 0.216 mmol, 1 equiv.), MeCN (36 mL), DMF (9 mL), HATU (124 mg, 0.326 mmol, 1.51 equiv.) and DIPEA (56 mg, 0.436 mmol, 2.02 equiv.) under nitrogen atmosphere. The resulting solution was stirred for 3 hr at room temperature. LCMS showed full conversation. The resulting mixture was concentrated. The crude product tert-butyl ((2 1S,2 4S,5 2R,5 3S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3-yl)carbamate was used directly for the next step without purification. LCMS (ESI): m/z [M+H] +=445.
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed crude mixture tert-butyl ((2 1S,2 4S,5 2R,5 3S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3-yl)carbamate (2 g, 4.499 mmol, 1 equiv.), DCM (120 mL), TFA (40 mL). The resulting solution was stirred for 1 hr at 25 degrees C. LCMS showed full conversation. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC to afford (2 1,S,2 4S,5 2R,5 3S)-5 3-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one 32.1 g (800 mg, 51.6%) as a solid. LCMS (ESI): m/z [M+H] +=345.
To (2 1S,2 4S,5 2R,5 3S)-5 3-amino-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one 32.1 g (900 mg, 2.613 mmol, 1 equiv.) and DIPEA (1.69 g, 13.064 mmol, 5 equiv.) in DCM (148 mL) was added MSCl (900 mg, 7.858 mmol, 3 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting solution was stirred for 2 hr at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×200 mL of dichloromethane, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC to afford racemic crude product (800 mg, 72.46%) as a solid. The crude product was purified by prep-SFC to afford N-((2 1S,2 4S,5 2R,5 3S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3-yl)methanesulfonamide (270.6 mg, 27.1%) as a solid and its enantiomer, N-((2 1R,2 4R,5 2S,5 3R)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3-yl)methanesulfonamide (361.4 mg, 36.1%) as a solid. LCMS (ESI): m/z calculated for C 21H 30N 2O 5S [M+H] +=423.19, found [M+H] +=423.15; 1H NMR (400 MHz, CDCl 3): δ 7.19 (td, J=7.7, 1.8 Hz, 1H), 7.11 (dd, J=7.5, 1.7 Hz, 1H), 6.96-6.86 (m, 1H), 6.77 (dd, J=8.0, 1.1 Hz, 1H), 5.24 (dd, J=9.8, 4.9 Hz, 1H), 5.14 (d, J=10.5 Hz, 1H), 4.34 (dd, J=14.1, 9.4 Hz, 2H), 3.84 (t, J=9.2 Hz, 1H), 3.73 (d, J=14.9 Hz, 3H), 3.60-3.46 (m, 2H), 3.09 (s, 3H), 2.77-2.49 (m, 2H), 2.33-2.16 (m, 1H), 2.06 (d, J=12.8 Hz, 2H), 2.00-1.82 (m, 2H), 1.68 (d, J=11.5 Hz, 2H), 1.10-1.45 (m, 4H).
The total synthesis of ALKS 2680 was originally reported in US2021/0155636 A1, beginning with a stereoselective reduction of ketone 4a to afford alcohol 5a(Scheme 1). The patented route employed L-selectride for facial selectivity.
To optimize this step, ChemAIRS proposed an alternative asymmetric hydrogenation utilizing an Ir/f-AmphBINOL catalyst system. This enantioselective methodology has demonstrated excellent control over both enantio- and diastereoselectivity, delivering chiral alcohols in up to 99% ee and a cis/trans ratio of 99:1. [DOI: 10.1021/acs.orglett.3c03550]
Another key transformation in the Alkermes route is the macrocyclization of intermediate 11a using HATU/DIPEA in a mixed MeCN/DMF solvent system to deliver macrocycle 12a.
The conversion of (pyridin-3-yl)methanesulfonamide 7a to (piperidin-3-yl)methanesulfonamide 8a was facilitated by Rh/C-catalyzed hydrogenation in EtOH/AcOH, followed by kinetic resolution using (+)-mandelic acid for stereochemical enrichment (WO2017/135306).
The macrocycle was constructed via intramolecular reductive etherification using Et₃SiH/TMSOTf in DCM (doi.org/10.1002/ejoc.201300135), providing the final scaffold in a late-stage cyclization strategy conducive to structural diversification.
Morse AM (May 2025). "Enhancing the Management of Hypersomnia: Examining the Role of the Orexin System". Seminars in Neurology. 45 (3): 410–419. doi:10.1055/a-2589-3825. PMID40239951.
(S)-({2-(2-aminopyridin-4-yl)-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}imino)(cyclopropyl)(methyl)-λ6 -sulfanone serine/threonine kinase inhibitor, antineoplastic, ART 0380, EX-A9085
Alnodesertib (formerly known as ART0380) is an investigational, orally administered drug designed to treat various types of cancer. It is a selective inhibitor of ATR (Ataxia-Telangiectasia and Rad3-related protein), a key kinase involved in DNA repair and cell cycle progression.
Targets ATR Kinase: It selectively inhibits ATR, which cancer cells rely on to fix DNA damage caused by rapid replication.
Blocks Signaling: By blocking the phosphorylation of CHK1, it prevents the activation of DNA damage checkpoints.
Induces Apoptosis: Inhibiting these repair pathways prevents cancer cells from surviving replication stress, ultimately leading to cell death (apoptosis).
Clinical Status and Indications
As of early 2026, alnodesertib is undergoing several clinical trials:
Metastatic Colorectal Cancer (mCRC): The FDA granted Fast Track designation in September 2025 for alnodesertib in combination with irinotecan for adult patients with ATM-negative mCRC in the third-line setting.
Ovarian Cancer: In March 2026, Artios Pharma reported that a Phase 2a study reached its primary endpoint, showing that adding a low dose of alnodesertib to gemcitabine improved progression-free survival in patients with platinum-resistant high-grade serous ovarian carcinoma (HGSOC).
Other Solid Tumours: It is being evaluated in the ongoing STELLA Phase 1/2a study for its potential across multiple solid tumour types characterized by high replication stress.
[0648] Synthesis is similar to that described for Example 24. The mixture of diastereomers (26.8 mg, 0.069 mmol) was separated by Chiral SFC (Mobile phase: n-hexane (0.1% DEA):EtOH(0.1% DEA) = 70:30; Flow rate: 80 g / min; 20 min; Column temperature: 35 °C; Back pressure: 100 bar; Column: Gilson-281, AY 20 x 250mm, 10 μm) to afford the two diastereomers of unknown absolute stereochemistry at the sulfur atom, title compounds 39a (6.6mg, 25% yield, >99% ee) as a white solid and 39b (7.1mg, 27% yield, >99% ee) as a white solid.
