Elironrasib

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Elironrasib

CAS 2641998-63-0

MFC55H78FN9O8 MW 1012.3 g/mol

1-[4-(dimethylamino)-4-methylpent-2-ynoyl]-N-[(2S)-1-[[(6S,8S,14S)-22-ethyl-21-[2-[(1S)-1-methoxyethyl]-3-pyridinyl]-18,18-dimethyl-9,15-dioxo-5,16-dioxa-2,10,22,28-tetrazapentacyclo[18.5.2.1^2,6.1^10,14.0^23,27]nonacosa-1(26),20,23(27),24-tetraen-8-yl]amino]-3-methyl-1-oxobutan-2-yl]-4-fluoro-N-methylpiperidine-4-carboxamide

Kirsten rat sarcoma viral oncogene homolog inhibitor, antineoplastic, RMC-6291, RMC 6291, 942KVV5CJP

Elironrasib (RMC-6291) is an investigational, orally bioavailable, RAS(ON) G12C-selective inhibitor developed by Revolution Medicines that targets the active GTP-bound form of KRAS G12C. In Phase 1 trials, it showed significant promise in treating advanced KRAS G12C-mutated solid tumors, including non-small cell lung cancer (NSCLC). [1, 2, 3]

Key Clinical Trial Results (as of Oct 2025):

Response Rate: 42% objective response rate (ORR).
Disease Control: 79% disease control rate (DCR).
Durability: Median duration of response was 11.2 months.
Survival: Median progression-free survival was 6.2 months.
Overcoming Resistance: Demonstrated efficacy in patients who had previously progressed on first-generation KRAS G12C(OFF) inhibitors.

Mechanism of Action:
Elironrasib acts as a covalent tri-complex inhibitor (TCI). It forms a complex with the intracellular chaperone protein cyclophilin A (CypA) and the active KRAS G12C(GTP) protein, effectively shutting down oncogenic signaling.

Development Status:

Designation: It has received FDA breakthrough therapy designation for KRAS G12C-mutant NSCLC.
Trials: Currently in Phase 1 clinical trials (e.g., NCT05462717) to evaluate safety, tolerability, and efficacy, both as a monotherapy and in combination.
Target Population: Patients with KRAS G12C-addicted solid tumors.

Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers – PubMed27 Mar 2025 — This information does not constitute medical advice or diagnosis. Elirronrasib (RMC-6291) is a potent, orally bioavailable,

Revolution Medicines to Present Updated Elironrasib Safety and Efficacy Data in Patients with KRAS G12C Non-Small Cell Lung Cancer Following Treatment with a KRAS(OFF) G12C Inhibitor22 Oct 2025 — This information does not constitute medical advice or diagnosis. Elirronrasib is a RAS(ON) G12C-selective inhibitor being develop…Revolution Medicines
Elironrasib May Overcome Resistance to Prior KRAS G12C Inhibition in Non-small Cell Lung Cancer

OriginatorREVOLUTION Medicines
ClassAntineoplastics; Morpholines; Piperidines; Pyridazines; Small molecules
Mechanism of ActionKRAS protein inhibitors
Phase I/IISolid tumours
Clinical Phase UnknownNon-small cell lung cancer
30 Jan 2026Phase-I/II clinical trials in Solid tumours (Combination therapy, Late-stage disease, Metastatic disease) in USA (PO) (NCT07397338)
31 Oct 2025Elironrasib is still in phase I trial in Solid tumours (Late-stage disease, Metastatic disease, Monotherapy) in Australia, Italy, South Korea, Malaysia, Singapore, Spain, Czech Republic, Thailand and USA (PO, Tablet) (NCT05462717)
28 Oct 2025No recent reports of development identified for phase-I development in Solid-tumours(Late-stage disease, Metastatic disease, Monotherapy) in Australia, Italy, South Korea, Malaysia, Singapore, Spain, Czech Republic, Thailand (PO, Tablet)

Elironrasib is an orally bioavailable, covalent inhibitor of the active, guanosine triphosphate (GTP)-bound form of the oncogenic KRAS substitution mutation G12C, KRAS G12C(ON), with potential antineoplastic activity. Upon oral administration, elironrasib forms a tri-complex with the intracellular chaperone protein and immunophilin cyclophilin A (CypA) and KRAS G12C(ON). This tri-complex inhibits KRAS G12C(ON)-mediated signaling, which may inhibit tumor cell proliferation. KRAS, a member of the RAS family of oncogenes, serves an important role in cell signaling, division and differentiation. Mutations of KRAS may induce constitutive signal transduction leading to tumor cell growth, proliferation, invasion, and metastasis.

Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Participants With Advanced KRAS G12C Mutant Solid TumorsCTID: NCT06128551Phase: Phase 1/Phase 2Status: RecruitingDate: 2026-04-23
Dose Escalation and Dose Expansion Study of RMC-6291 Monotherapy in Subjects With Advanced KRASG12C Mutant Solid TumorsCTID: NCT05462717Phase: Phase 1Status: Active, not recruitingDate: 2026-04-08
Study of RAS(ON) Inhibitors in Combination With Ivonescimab in Patients With Solid TumorsCTID: NCT07397338Phase: Phase 1/Phase 2Status: RecruitingDate: 2026-03-30
Study of RAS(ON) Inhibitors in Patients With Advanced RAS-mutated NSCLCCTID: NCT06162221Phase: Phase 1/Phase 2Status: RecruitingDate: 2026-03-09

SYN

https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02313

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023205701&_cid=P10-MOXQ72-19496-1

PAT’

https://patentscope.wipo.int/search/en/detail.jsf?docId=US443002383&_cid=P10-MOXQ72-19496-1

Part 5—Synthesis of Compound A—(1²M)-1-(4-(dimethylamino)-4-methylpent-2 ynoyl)-N-((2S)-1-(((2²S,6³S,4S)-1¹-ethyl-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6¹,6²,6³,6⁴,6⁵,6⁶-hexahydro-1¹H-8-oxa-2(4,2)-morpholina-1(5,3)-indola-6(1,3) pyridazinacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2 yl)-4-fluoro-N-methylpiperidine-4-carboxamide

To a 50 L glass reactor was charged Compound 15 (1.91 kg, 1.0 eq) and DMF (13.9 kg). The mixture was agitated at 20-30° C. until all of the solids were dissolved. Compound 2 (1.70 kg, 1.2 eq) and DMF (3.8 kg) were charged. The mixture was agitated at 20-30° C. until all of the solids were dissolved. DIPEA (2.20 kg, 5.50 eq) was charged at 20-30° C. and the mixture was cooled to −20-−10° C. under agitation. Ethyl cyanoglyoxylate-2-oxime (Oxyma) (0.48 kg, 1.1 eq) was charged to the reactor and the reaction mixture was agitated at −20 to −10° C. for 30 min. PyBOP was charged as a DMF solution (1.89 kg dissolved in 3.62 kg DMF, 1.2 eq) to the reactor at −20 to −10° C. in </=1 h. The reaction mixture was agitated at −20 to −10° C. for 1-3 h. Reaction monitoring by HPLC showed the reaction was complete.

The crude reaction mixture was diluted with EtOAc (3.6 kg) and partitioned with a mixture of EtOAc (65 kg) and brine (25 wt %, 132 kg). The biphasic mixture was agitated at 20-30° C. for 1 h and filtered through a pad of diatomite. EtOAc (11 kg) was used to rinse the reactor and spent filter aid wet cake. The combined filtrates were allowed to stand for 1 h before the phases were separated. The organic layer was washed once with brine (25 wt %, 90 kg×2). HCl (0.6 M aqueous solution, 71 kg) was charged to the isolated organic layer at 5-20° C. The biphasic mixture was agitated at 10-20° C. for 1 h. The phases were separated, and the upper lean organic phase was extracted with HCl (0.6 M aqueous solution, 30 kg). The combined rich aqueous phases were washed three times with EtOAc (34 kg×3). To the washed aqueous phase was charged EtOAc (34 kg) and the pH was adjusted to pH 9-10 by charging Na ₂CO ₃aqueous solution (30 wt %) at 10-20° C. The mixture was agitated at 10-20° C. for 1 h and the phases were separated. The lean aqueous phase was extracted with EtOAc (34 kg), and the combined rich organic phases were washed twice with brine (25 wt %, 90 kg×2). The resulting organic layer was then washed with a solution of acetic acid in brine (prepared by dissolving 0.23 kg glacial acetic acid and 8 kg 25 wt % brine in 115 kg water) (39 kg×2), a solution of Na ₂CO ₃in brine (prepared by dissolving 1.3 kg Na ₂CO ₃and 8 kg 25 wt % brine in 31 kg water) (40 kg), and brine (25 wt %, 92 kg), respectively. The crude organic solution was then treated with CUNO® by filtering through a cartridge and the filtrate was concentrated under reduced pressure at NMT 40° C. to ˜30 L. The crude residue was then crystallized by charging n-heptane (57 kg) with seed (0.040 kg).

The crude product was then further purified by recrystallization with a mixture of EtOAc and n-Heptane to give purified Compound A as a white solid.

HRMS (ESI+)Calculated for C₅₅H₇₈FN₉O₈(M+H): 1012.6036Found: 1012.6065

1H NMR (400 MHz, CD ₃OD, 23° C.)δ8.71 (dd J=4.8, 1.6 Hz, 1H), 7.83 (d, J=7.2 Hz, 1H), 7.50 (dd, J=8.0, 4.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 7.07 (dd, J=9.0, 2.0 Hz, 1H), 5.67 (d, J=8.8 Hz, 1H), 4.62 and 4.52 (d, J=10.0 Hz, 1H, as rotamers), 4.46 (d, J=12.4 Hz, 1H), 4.28-4.37 (m, 2H), 4.24 (q (J=6.4 Hz, 1H), 4.12-4.17 (m, 1H), 3.50-4.00 (m, 9H), 3.28 (d, J=10.8 Hz, 1H), 3.10-3.20 and 2.90-3.00 (m, 8H, as rotamers), 2.60-2.80 (m, 4H), 2.35 (s, 3H), 2.34 (s, 3H), 2.05-2.35 (m, 7H), 1.85-1.95 (m, 2H), 1.60-1.73 (m, 2H), 1.46 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H), 0.96 and 1.02 (d, J=6.4 Hz, 3H, as rotamers), 1.00-1.10 (m, 3H), 0.83 and 0.87 (dd, J=6.8, 2.0 Hz, 3H, as rotamers), (0.77 (bs, 3H), 0.64 (bs, 3H)