Dabogratinib

 

Dabogratinib

CAS 2800223-30-5

MF C25H24Cl2N6O3S, 559.5 g/mol

5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridinyl]-1H-indazole

(R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole

[6-(5-{5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-1H-indazol-3-yl}pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl](methyl)-λ6sulfanedioneTYRA-300
fibroblast growth factor receptor inhibitor, antineoplastic, TYRA-300, TYRA 300, A1AV2, FH245S2JZJ

Dabogratinib (TYRA-300) is an orally active, highly selective inhibitor of fibroblast growth factor receptor 3 (FGFR3), designed to treat cancers with FGFR3 alterations and genetic diseases like achondroplasia. It shows potent tumor growth inhibition in preclinical studies and early phase I/II (SURF301) clinical activity against advanced bladder cancer and metastatic urothelial carcinoma. 

Key Aspects of Dabogratinib (TYRA-300)

• Mechanism: It acts as a selective inhibitor of FGFR3 with a high selectivity over other isoforms (FGFR1/2/4), which helps minimize toxicity.
• Target Indications: It is being developed for FGFR3-mutant cancers, including non-muscle invasive bladder cancer (NMIBC) and metastatic urothelial carcinoma, as well as pediatric achondroplasia.
• Preclinical Performance: Studies showed that it reduces tumor growth and drives tumor regression, especially in xenograft models with FGFR3-activating mutations (e.g., S249C).
• Clinical Trials:
  • SURF301 (Phase I/II): Ongoing study, Tyra Biosciences reported early efficacy in patients with advanced metastatic urothelial carcinoma (mUC) harboring FGFR3 mutations/fusions.
  • SURF302 (Phase II): Evaluating the drug in patients with FGFR3-altered, low-grade, intermediate-risk non–muscle invasive bladder cancer (NMIBC).
  • BEACH301 (Phase II): Studying the drug in children with achondroplasia, as it is designed to increase long-bone growth.
• Properties: It is an orally bioavailable molecule with an IC50 of  for FGFR3. 

Dabogratinib is an orally bioavailable, selective inhibitor of human fibroblast growth factor receptor 3 (FGFR3), with potential antineoplastic activity. Upon oral administration, dabogratinib specifically targets and binds to certain FGFR3 activating gene alterations, and specifically the gatekeeper mutants V555L/M. This blocks FGFR3-mediated signaling and leads to an inhibition of tumor cell proliferation in FGFR3-overexpressing cells. FGFR3, a receptor tyrosine kinase, is involved in angiogenesis and in the proliferation, differentiation, and survival of tumor cells. FGFR3 expression is associated with poor prognosis. It is overexpressed by certain tumor cell types.

• Efficacy and Safety of TYRA-300 in Participants With FGFR3 Altered Low Grade, Intermediate Risk Non-Muscle Invasive Bladder CancerCTID: NCT06995677Phase: Phase 2Status: RecruitingDate: 2026-04-09
• A Study of TYRA-300 in Children With Achondroplasia: BEACH301CTID: NCT06842355Phase: Phase 2Status: RecruitingDate: 2026-03-06
• Safety and Preliminary Anti-Tumor Activity of TYRA-300 in Advanced Urothelial Carcinoma and Other Solid Tumors With FGFR3 Gene AlterationsCTID: NCT05544552Phase: Phase 1/Phase 2Status: Active, not recruitingDate: 2026-01-12

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US426725073&_cid=P21-MO801L-81314-1

Example 46. 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole

 (5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1H-indazole. Triethylamine (20.5 uL, 0.148 mmol, 1.2 equiv) and methylsulfonyl chloride (9.5 uL, 0.123 mmol, 1.0 equiv) were sequentially added at room temperature to a solution of example 45 (59.0 mg, 0.123 mmol, 1 equiv) in anhydrous THE (3 mL). After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure on to Celite (1 g). The product was purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge), eluting with a gradient of 0 to 100% acetonitrile in water. The fractions containing product were collected and lyophilized to give a white solid (45.0 mg, 65% yield). Analysis: LCMS: m/z=559.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 13.02 (br s, 1H), 8.59 (s, 2H), 8.52 (dd, J=0.6, 2.2 Hz, 1H), 7.87 (dd, J=2.4, 8.6 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.09 (dd, J=2.3, 9.0 Hz, 1H), 6.54 (dd, J=0.4, 8.6 Hz, 1H), 6.10 (q, J=6.6 Hz, 1H), 4.17 (s, 4H), 4.12 (s, 4H), 3.03 (s, 3H), 1.76 (d, J=6.6 Hz, 3H).

PAT

• Indazole compoundsPublication Number: TW-202241906-APriority Date: 2020-12-30
• Indazole compounds as kinase inhibitorsPublication Number: EP-4271673-A1Priority Date: 2020-12-30
• Indazole compounds as kinase inhibitorsPublication Number: WO-2022147246-A1Priority Date: 2020-12-30
• Indazole compounds as kinase inhibitorsPublication Number: US-12264149-B2Priority Date: 2020-12-30Grant Date: 2025-04-01
• Polymorphic compounds and uses thereofPublication Number: EP-4547670-A1Priority Date: 2022-06-29
• Indazole compounds as kinase inhibitorsPublication Number: US-12071428-B2Priority Date: 2020-12-30Grant Date: 2024-08-27
• Indazole Compounds as Kinase InhibitorsPublication Number: KR-20230152654-APriority Date: 2020-12-30
• Indazole compounds as kinase inhibitorsPublication Number: US-2024109865-A1Priority Date: 2020-12-30
• Indazole compounds as kinase inhibitorsPublication Number: US-2024208941-A1Priority Date: 2020-12-30
• Tyra-300 (5-[(1r)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridyl]-1h-indazole ) in combination with a pd-1 or pd-l1 antagonist for use in the treatment of cancerPublication Number: WO-2025064744-A1Priority Date: 2023-09-22
• Fgfr inhibitors and methods of use thereofPublication Number: WO-2025061029-A1Priority Date: 2023-09-18
• Polymorphic compounds and uses thereofPublication Number: AU-2023300357-A1Priority Date: 2022-06-29
• Polymorphic compounds and uses thereofPublication Number: WO-2024006883-A1Priority Date: 2022-06-29
• Polymorphic compounds and uses thereofPublication Number: TW-202408493-APriority Date: 2022-06-29

ADVT

ANAX LABORATORIES

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References

Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia

Publication Name: Journal of Medicinal Chemistry

Publication Date: 2024-09-11

PMID: 39258897

DOI: 10.1021/acs.jmedchem.4c01531

////////dabogratinib, anax lab, fibroblast growth factor receptor inhibitor, antineoplastic, TYRA-300, TYRA 300, A1AV2, FH245S2JZJ

#dabogratinib, #anax lab, #fibroblast growth factor receptor inhibitor, #antineoplastic, #TYRA-300, #TYRA 300, #A1AV2, #FH245S2JZJ

Danifexor

 

Danifexor

CAS 2648738-68-3

MF C29H20Cl2N2O5 MW547.386

6-[6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]naphthalen-2-yl]oxypyridine-3-carboxylic acid

3-Pyridinecarboxylic acid, 6-[[6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]-2-naphthalenyl]oxy]-

farnesoid X receptor agonist, TUU8G1CX9O, HEC 96719, ASC42 

Danifexor is an investigational drug that acts as a potent and selective agonist for the farnesoid X receptor (FXR). It was primarily being developed for the treatment of liver diseases such as Primary Biliary Cholangitis (PBC). ProbeChem +1

However, recent reports from April 2024 indicate that development for Danifexor has been discontinued because it was deemed non-competitive against other emerging therapies for PBC. 

Key Properties and Identifiers

Danifexor is a non-steroidal molecule with specific chemical markers used in laboratory research:

• Target: Farnesoid X receptor (FXR).

Therapeutic Context

The drug was designed to target the FXR pathway, which regulates bile acid, lipid, and glucose metabolism. 

• Primary Goal: Treatment of Primary Biliary Cholangitis (PBC), a chronic liver disease.
• Mechanism: As an agonist, it binds to and activates FXR to help reduce the toxic buildup of bile acids in the liver.

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=US380594531&_cid=P21-MOAUR7-95920-1

Example 1

Preparation of 6-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methoxy)naphthalen-2-yl)oxy)nicotinic acid (Compound 1)

(a) Referring to the following reaction equation (Route A), Compound 1A-1 (1.0 g, 2.88 mmol, 1 eq.), Compound 1A-2 (0.46 g, 2.88 mmol, 1 eq.) and cesium carbonate (1.88 g, 5.76 mmol, 2 eq.) were dissolved in DMF (10 ml). The reaction was carried out at 65° C. for 2 h. After cooling, 10 ml water and 10 ml EA (ethyl acetate) were added for extraction, and the organic phase was washed with water and concentrated to dryness to give Compound 1A, 6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)naphthalen-2-ol, 0.8 g, yield: 65.0%. LCMS (ESI): calculated for C ₂₃H ₁₇C ₁₂NO ₃; [M+H] ⁺: 426.1, found: 426.1.

b) Referring to the following reaction equation, Compound 1A (0.2 g, 0.47 mmol, 1 eq.), 6-bromonicotinic acid methyl ester (0.1 g, 0.47 mmol, 1 eq.) and cesium carbonate (0.306 g, 0.94 mmol, 2 eq.) were dissolved in DMF (10 ml). The reaction was carried out at 65° C. for 2 h. After cooling, 10 ml water and 10 ml EA were added for extraction, and the organic phase was washed with water and concentrated to dryness to give Compound 1B, methyl 6((6((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)naphthalene-2-yl)oxy)nicotinate, 0.21 g, yield: 80.0%. LCMS (ESI): calculated for C ₃₀H ₂₂C ₁₂N ₂O ₅; [M+H] ⁺: 561.1, found: 561.1.

(c) Referring to the following reaction equation, compound 1B (100 mg) was dissolved in methanol (2 ml), then 10% NaOH aqueous solution (1 ml) was added, the temperature was raised to 60° C., and the reaction was carried out for 1 h. The pH of the reaction solution was adjusted to 2 to 4 by adding 1N HCl solution, and 10 ml EA (ethyl acetate) was added for extraction. The organic phase was concentrated and purified on a column (PE/EA/AcOH=1/1/01 elution, wherein PE is petroleum ether) to give the title compound 1 (36 mg, yield: 37.0%).

1H NMR (400 MHz, DMSO-d 6) δ 8.57 (s, 1H), 8.23 (d, J=7.2 Hz, 1H), 7.74 (dd, J=2.0, 8.8 Hz, 2H), 7.60 (d, J=7.6 Hz, 2H), 7.56 (s, 1H), 7.51 (dd, J=8.8, 7.2 Hz, 1H), 7.33 (s, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.93 (d, J=6.4 Hz, 1H), 4.98 (s, 2H), 2.57-2.50 (m, 1H), 1.19-1.11 (m, 4H). LCMS (ESI): calculated for C 29H 20Cl 2N 2O 5; [M+H] +: 547.1, found: 547.1. 13C NMR (400 MHz, DMSO-d 6) δ7.79, 8.87, 8.87, 59.31, 107.74, 110.05, 110.97, 117.64, 119.43, 122.52, 127.55, 128.64, 128.89, 128.89, 129.18, 129.67, 131.73, 131.79, 132.94, 135.10, 135.10, 141.20, 149.11, 150.73, 155.79, 159.68, 163.82, 167.81, 172.61. IR (cm −1): major stretches at 1591.94 (C═O stretch), 1412.27, 1556.70 (C—C stretch), 1364.37, 1389.89 (C—H deformation), 1218.41, 1250.94 (C═N stretch), 791.88 (C—Cl stretch).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021109712&_cid=P21-MOAUXW-99264-1

PAT

• Use and pharmaceutical composition of phenylisoxazolyl methylene-naphthalene-ether derivativesPublication Number: WO-2021109713-A1Priority Date: 2019-12-03
• Compounds for modulating activity of fxr and uses thereofPublication Number: WO-2021109712-A1Priority Date: 2019-12-03
• Uses and pharmaceutical compositions of phenylisoxazolylmethylene-naphthalene-ether derivativesPublication Number: CN-112891348-APriority Date: 2019-12-03
• Compounds that modulate FXR activity and their applicationsPublication Number: CN-112898289-APriority Date: 2019-12-03
• Compounds that modulate FXR activity and their applicationsPublication Number: CN-112898289-BPriority Date: 2019-12-03Grant Date: 2022-11-04
• Uses and pharmaceutical compositions of phenylisoxazolyl methylene-naphthalene-ether derivativesPublication Number: KR-20220101697-APriority Date: 2019-12-03
• Compounds for modulating activity of fxr and uses thereofPublication Number: EP-4073070-A1Priority Date: 2019-12-03
• Use and pharmaceutical composition of phenylisoxazolyl methylene-naphthalene-ether derivativesPublication Number: EP-4073071-A1Priority Date: 2019-12-03
• Compounds for modulating activity of fxr and uses thereofPublication Number: WO-2021108974-A1Priority Date: 2019-12-03

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References

////////danifexor, ANAX LAB, farnesoid X receptor agonist, TUU8G1CX9O, HEC 96719, ASC42

#danifexor, #ANAX LAB, #farnesoid X receptor agonist, #TUU8G1CX9O, #HEC 96719, #ASC42

Daraxonrasib

 

Daraxonrasib

CAS 2765081-21-6

8/26/2026, FDA APPROVED 2026, FDA 2026, Rasonque

MFC44H58N8O5S MW811.0 g/mol

trans-(1S,2S)-N-[(7S,13S)-21-ethyl-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridinyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetrazapentacyclo[17.5.2.1^2,5.1^9,13.0^22,26]octacosa-1(25),2,5(28),19,22(26),23-hexaen-7-yl]-2-methylcyclopropane-1-carboxamide

Kirsten rat sarcoma viral oncogene homolog inhibitor, antineoplastic, RMC-6236, RMC 6236, B6T47Y2UAP, RAS-IN-2,

To treat metastatic pancreatic cancer

Daraxonrasib (formerly RMC-6236) is an investigational, orally administered "molecular glue" RAS inhibitor developed by Revolution Medicines for treating advanced solid tumors with RAS mutations, particularly metastatic pancreatic cancer. April 2026 Phase 3 trials showed it significantly improves survival, demonstrating high potential as a first-line treatment. 

Key Clinical Findings and Updates (as of April 2026):

• Mechanism: It acts as a RAS(ON) inhibitor, targeting mutated and wild-type RAS proteins () to disrupt cancer signaling.
• Breakthrough Results: Data from the RASolute 302 trial showed a substantial survival benefit in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC).
• High Response Rates: In trials, daraxonrasib combined with chemotherapy showed a 58% confirmed objective response rate (ORR) and 84% progression-free survival (PFS) at 6 months in untreated RAS-mutant metastatic pancreatic cancer.
• Safety Profile: Generally well-tolerated, with side effects including rash, diarrhea, stomatitis, and nausea.
• Recognition: Named the "2025 Molecule of the Year" by Drug Hunter for its, novel mechanism and clinical potential. 

Daraxonrasib is currently being studied in the Phase 3 RASolute 303 trial for first-line treatment of pancreatic cancer.

Daraxonrasib (RMC-6236) is a RAS inhibitor drug. It is undergoing testing by Revolution Medicines to treat advanced solid tumors with RAS mutations, especially metastatic pancreatic ductal adenocarcinoma (PDAC) containing KRAS G12X mutations.^[1] It received a breakthrough therapy designation from the U.S. Food and Drug Administration.^[2]

Daraxonrasib is orally active and multi-selective RAS inhibitor. It uses a tri-complex mechanism to target the active, GTP-bound form of RAS proteins, including mutant and wild-type forms. Unlike conventional RAS inhibitors, it first binds to the chaperone-like protein cyclophilin A to form a complex, which then attaches to active RAS. This interaction blocks downstream effector binding and inhibits oncogenic signaling.^[3]

In 2026, Daraxonrasib clinical trial completed a phase 3 clinical trial (RASolute 302) to assess efficacy compared to standard-of-care chemotherapy.^[4] The trial met all primary and key secondary endpoints, including progression-free survival (PFS). The company reported median survival of 13.2 months with daraxonrasib vs. 6.7 months with standard chemotherapy. The hazard ratio for death was 0.40 (a 60% reduction in risk of death; p < 0.0001). Daraxonrasib was generally well tolerated with a manageable safety profile and no new safety signals.^[5]

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024216048&_cid=P20-MODPOO-66335-1

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024216017&_cid=P20-MODPOO-66335-1

PATENT ATTORNEY DOCKET: 51432-038WO2 Part 4 – Purification of Compound A - (1S,2S)-N-[(7S,13S)-21-ethyl-20-{2-[(1S)-1- methoxyethyl]-5-(4-

1.0equiv) at 25°C. The resulting suspension was stirred until solids were completely dissolved. The resulting methanol solution was filtered through microporous filter and transferred to another reactor. Then the reactor temperature was maintained at 25°C and slowly water (2.41kg, 1.0 V) water was added over a period of 30 minutes. The resulting cloudy solution was stirred for another 30 minutes at 25°C. Then a solution of methanol and water (3.42kg, 1:2, v/v) slowly over 1 hour. The resulting suspension was stirred for 2 hours at 25°C. Again, to the suspension additional water (2.48kg) slowly added over 1 hour. The final, suspension was stirred for additional 1 hour. Water (9.29kg, 3.75 V) was added to the suspension slowly over 2 hours and the mixture was stirred for at least for 16 hours at 25°C. The resulting suspension was filtered and washed with mixed solvent water: MeOH (3:2, v/v) twice (2x 2.2 kg), followed by water (4.91kg) washing. The wet cake was dried under reduced pressure and controlled humidity (temperature: 25 ± 5 ˚C, vacuum ≥ -0.085 MPa, humidity: 10%~20%) for 37 hours to afford Compound A as a white solid (2.68 kg, 99.4% a/a purity, 93.0% w/w assay, KF: 6.7%, 3.07 mol, 92% yield, Table 27).

PAT

• Synthesis of ras inhibitorsPublication Number: WO-2024216017-A2Priority Date: 2023-04-14
• Macrocycle compounds useful as kras inhibitorsPublication Number: WO-2024008834-A1Priority Date: 2022-07-08
• Ras inhibitorsPublication Number: US-11690915-B2Priority Date: 2020-09-15Grant Date: 2023-07-04
• Ras inhibitorsPublication Number: US-2023226186-A1Priority Date: 2020-09-15

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References

References

1.  Cregg J, Edwards AV, Chang S, Lee BJ, Knox JE, Tomlinson AC, et al. (March 2025). "Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers". Journal of Medicinal Chemistry. 68 (6): 6064–6083. doi:10.1021/acs.jmedchem.4c02314. PMID 40056080.
2.  Sava J (July 1, 2025). "Daraxonrasib Earns FDA Breakthrough Status in Pancreatic Cancer". Targeted Oncology. Retrieved October 12, 2025.
3.  Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, et al. (June 2024). "Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers". Cancer Discovery. 14 (6): 994–1017. doi:10.1158/2159-8290.CD-24-0027. PMC 11149917. PMID 38593348.
4.  Clinical trial number NCT05379985 at ClinicalTrials.gov
5.  Mast J (2026-04-13). "Revolution Medicines touts 'unprecedented' data for pancreatic cancer pill". STAT. Retrieved 2026-04-13.

Clinical data
Other names	RMC-6236
Identifiers
IUPAC name
CAS Number	2765081-21-6
PubChem CID	164726578
IUPHAR/BPS	13368
ChemSpider	115275938
UNII	B6T47Y2UAP
KEGG	D13265
ChEBI	CHEBI:746946
Chemical and physical data
Formula	C44H58N8O5S
Molar mass	811.06 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

//////////daraxonrasib, anax labs, Kirsten rat sarcoma viral oncogene homolog inhibitor, antineoplastic, RMC-6236, RMC 6236, B6T47Y2UAP, RAS-IN-2, FDA APPROVED 2026, FDA 2026, Rasonque

#daraxonrasib, #anax labs, #Kirsten rat sarcoma viral oncogene homolog inhibitor, #antineoplastic, #RMC-6236, #RMC 6236, B6T47Y2UAP, #RAS-IN-2, #APPROVALS 2026, #FDA 2026, #Rasonque

ANAX LABORATORIES

WEBSITE https://www.anaxlab.com/

Discovery Solutions, Supporting the chemistry needs of clients in the Medical, Analytical and Bio Sciences

Development Solutions, Developing from Lab scale to PR&D, Kilo Scale-ups and Commercial Scales

SEE MORE.........Integrated Solutions, Manufacturing Solutions, Products,
Can't Find? Let's Connect

Phone : +91 897704 2010 /  +91 9177075735, Email : info@anaxlab.com

#MedicinalChemistry, #DrugDiscovery, #OrganicSynthesis, #ChemicalLibrary, #BuildingBlocks, #SARStudies, #ChemistryInnovation, #medchem, #Drugdevelopment, #Biotech, #Biotechnology, #AnaxLaboratories, #Pharma

.

Darlifarnib

 

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

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