Darlifarnib

CAS 2939824-30-1

MF C29H20N6O MW 468.51

14-amino-14-(3-methylimidazol-4-yl)-7-oxa-19-azapentacyclo[13.6.2.1^2,6.1^9,13.0^18,22]pentacosa-1(22),2(25),3,5,9,11,13(24),15(23),16,18,20-undecaene-10,20-dicarbonitrile

farnesyl transferase inhibitor, antineoplastic, KO-2806, KO 2806, T206317

Darlifarnib (KO-2806) is an investigational, orally active next-generation farnesyl transferase inhibitor (FTI) being developed by Kura Oncology to treat solid tumors, such as clear cell renal cell carcinoma (ccRCC). It inhibits the enzyme farnesyl transferase, blocking KRAS and mTORC1 signaling to induce tumor regression. It is often combined with other agents to overcome resistance. 

Key Details About Darlifarnib

• Mechanism of Action: As a FTI, darlifarnib binds to and inhibits farnesyl transferase, which prevents the activation of RAS oncogenes and inhibits downstream mTORC1 signaling, leading to tumor cell death.
• Target Indications: Preclinical and early clinical data show potential in treating KRAS-mutant cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and clear cell renal cell carcinoma (ccRCC).
• Combination Therapy: Data from the Phase 1 FIT-001 trial (presented in April 2026) showed that combining darlifarnib with the TKI cabozantinib demonstrated robust activity in patients with pretreated, advanced ccRCC.
• Overcoming Resistance: Darlifarnib is designed to re-sensitize tumors that have become resistant to prior therapies, such as RAS inhibitors and tyrosine kinase inhibitors (TKIs).
• Status: It is an investigational drug and not yet FDA-approved. 

• OriginatorKura Oncology
• ClassAntineoplastics; Small molecules
• Mechanism of ActionFarnesyltranstransferase inhibitors
• Phase IAdenocarcinoma; Colorectal cancer; Non-small cell lung cancer; Renal cell carcinoma; Solid tumours
• 12 Jan 2026Kura Oncology plans the one or more expansion cohorts of KO 2806 and cabozantinib in patients with advanced renal cell carcinoma in the first half of 2026
• 22 Oct 2025Pharmacodynamics data from a preclinical trial in Cancer presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2025 (AACR-NCI-EORTC-2025)
• 18 Oct 2025Adverse events and efficacy data from a phase I trial in Non-small cell lung cancer, Renal cell carcinoma, Adenocarcinoma released by Kura Oncology

PAT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=EB1BA4690FD8B3EC201C8F26854E2D57.wapp2nA?docId=US467104302&_cid=P20-MOGKLM-59141-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US437765371&_cid=P20-MOGKQ9-61489-1

Step A: Preparation of (058-1)

Compound 054 (1.2 g, 2.61 mmol) was mixed with POCl3 (19.80 g, 129.13 mmol, 12.00 mL) at 25° C. The mixture was stirred at 100° C. for 1 h. The mixture was concentrated. To the residue was added NaOH (1 M in H 2O, 100 mL). The aqueous layer was extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and the filter cake was washed with EtOAc (20 mL). The combined filtrates were concentrated. The crude product was blended with another batch prepared from 0.5 g of 054. The crude product was purified by flash chromatography on silica gel (MeOH in DCM=0 to 10%) to give 058-1 (1.3 g, 2.71 mmol, 73.35% yield) as a yellow solid. LCMS R t=1.79 min in 3.0 min chromatography, 10-80 CD, ESI calcd. for C 28H 20ClN 4O 2 [M+H] + 479.1, found 479.1.

Step B: Preparation of (058-2)

To a solution of 058-1 (1.2 g, 2.51 mmol) in DMF (10 mL) was added Zn(CN)2 (2.69 g, 22.91 mmol, 1.45 mL) and Pd(PPh3)4 (579.07 mg, 501.12 μmol) in a three-neck bottom flask at 25° C. under N 2. The mixture was stirred at 100° C. for 2 h. The mixture was cooled to 25° C. and added into water (50 mL). The aqueous phase was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM=0 to 3%) to give 058-2 (900 mg, 1.92 mmol, 76.51% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6) δ=8.33-8.22 (m, 2H), 8.10 (s, 1H), 7.94-7.76 (m, 2H), 7.69 (s, 1H), 7.52-7.39 (m, 2H), 7.28-7.02 (m, 5H), 6.36 (s, 1H), 5.54 (s, 2H), 3.56 (s, 3H).

Step C: Preparation of (rac)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2²,4⁴-dicarbonitrile (rac-058)

To a solution of 058-2 (800 mg, 1.70 mmol) in DMI (8 mL) was added SOCl2 (1.01 g, 8.52 mmol, 618.05 μL). The mixture was stirred at 40° C. for 1 h. To NH 3 in MeOH (7 M, 100 mL) was added the above mixture at −10° C. The mixture was stirred at 25° C. for 30 min. The reaction mixture was poured into H 2O (100 mL). The aqueous layer was extracted with EtOAc (150 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and the filter cake was washed with EtOAc (20 mL). The combined filtrates were concentrated. The crude product was purified by flash chromatography on silica gel (MeOH in DCM=0 to 8%) to give rac-058 (550 mg, 1.17 mmol, 68.89% yield) as a yellow solid. LCMS R t=1.71 min in 3.0 min chromatography, 10-80CD, ESI calcd. for C 29H 21N 6O [M+H] + 469.2, found 469.2.

Step D: Preparation of (S)-3-amino-3-(1-methyl-1H-imidazol-5-yl)-6-oxa-2(4,6)-quinolina-1,4(1,3)-dibenzenacyclohexaphane-2²,4⁴-dicarbonitrile ((S)-058)

rac-058 (500 mg, 1.07 mmol) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 μm); mobile phase: [0.1% NH 3H 2O EtOH]; B %: 45%-45%) to give (S)-058 (229.5 mg, 489.85 μmol, 45.90% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d 6) δ=8.37 (d, J=8.4 Hz, 1H), 8.23 (d, J=9.2 Hz, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.48-7.19 (m, 4H), 7.18-7.04 (m, 2H), 6.44 (s, 1H), 5.64-5.45 (m, 2H), 3.48 (s, 3H), 3.18 (s, 2H). LCMS R t=1.68 min in 3.0 min chromatography, 10-80CD, ESI calcd. for C 29H 21N 6O [M+H] + 469.2, found 469.2. HPLC R t=3.03 min in 8 min chromatography, 220 nm, purity 100%. Chiral HPLC (S)-058: R t=2.44 min in 4 min (ee 99.54%) (AD_ETOH_DEA_5_40_4ML_4MIN_5CM), ((R)-058: R t=1.93 min (ee 99.44%)).

PAT

• Macrocyclic compounds and compositions, and methods of preparing and using the samePublication Number: US-2023322711-A1Priority Date: 2021-11-30
• Macrocyclic compounds and compositions, and methods of preparing and using the samePublication Number: US-12018011-B2Priority Date: 2021-11-30Grant Date: 2024-06-25

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References

/////////////darlifarnib, ANAX LAB, farnesyl transferase inhibitor, antineoplastic, KO-2806, KO 2806, T206317