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Darlifarnib

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Darlifarnib

CAS 2939824-30-1

MF C29H20N6O MW 468.51

14-amino-14-(3-methylimidazol-4-yl)-7-oxa-19-azapentacyclo[13.6.2.12,6.19,13.018,22]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

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References

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

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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