WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H205946
CAS#: 1234356-69-4
Description: Derazantinib, also known as ARQ-087, is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) with potential antineoplastic activity. FGFR inhibitor ARQ 087 binds to and potently inhibits the activity of FGFR subtypes 1, 2 and 3. This may result in the inhibition of FGFR-mediated signal transduction pathways, tumor cell proliferation, tumor angiogenesis and tumor cell death in FGFR-overexpressing tumor cells. FGFR, a receptor tyrosine kinase, is upregulated in many tumor cell types and plays a key role in tumor cellular proliferation, differentiation, angiogenesis and survival.
Hodoodo Cat#: H205946
Name: Derazantinib
CAS#: 1234356-69-4
Chemical Formula: C29H29FN4O
Exact Mass: 468.23
Molecular Weight: 468.576
Elemental Analysis: C, 74.34; H, 6.24; F, 4.05; N, 11.96; O, 3.41
Related CAS #: 1821329-75-2 (dihydrochloride) 1234356-69-4
Synonym: ARQ 087; ARQ087; ARQ-087; Derazantinib
IUPAC/Chemical Name: (6R)-6-(2-fluorophenyl)-N-(3-{2-[(2-methoxyethyl)amino]ethyl}phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine
InChi Key: KPJDVVCDVBFRMU-AREMUKBSSA-N
InChi Code: InChI=1S/C29H29FN4O/c1-35-16-15-31-14-13-20-7-6-8-22(17-20)33-29-32-19-21-18-26(24-10-4-5-12-27(24)30)23-9-2-3-11-25(23)28(21)34-29/h2-12,17,19,26,31H,13-16,18H2,1H3,(H,32,33,34)/t26-/m1/s1
SMILES Code: COCCNCCC1=CC(NC2=NC=C3C[C@@H](C4=CC=CC=C4F)C5=CC=CC=C5C3=N2)=CC=C1
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | Derazantinib (ARQ-087) is an inhibitor of the fibroblast growth factor receptor (FGFR) with IC50 values of 1.8 nM for FGFR2, and 4.5 nM for FGFR1 and 3. |
| In vitro activity: | FGFR pathway inhibition was examined in three solid tumor lines, the colorectal cancer cell line (NCI-H716), and gastric cancer cell lines (SNU-16 and KATO-III). As shown in Fig 3A, ARQ 087 inhibited the phosphorylation of FGFRs in all three cell lines. The mechanism by which ARQ 087 inhibits the growth of FGFR kinase dependent cell lines was also investigated. Treatment with ARQ 087 led to an accumulation of cells in the G1 phase cell cycle in a dose- and time-dependent manner (Fig 4A and Table 4). The sub-G1 population (Fig 4A) of NCI-H716 cells, increased after treatment with 1 μM of ARQ 087 (Fig 4A and Table 4). To investigate whether the disruption of the cell cycle correlated with an increase in apoptosis SNU-16 cells were treated with 1 μM of ARQ 087 for 0, 24, 48, and 72 hours, and X-linked inhibitor of apoptosis protein (XIAP), cleaved PARP, activated caspase 3, phospho-p53 were assessed by Western blotting analysis. A decrease in XIAP, and an increase in cleaved-PARP, activated-caspase 3, and pP53 were observed (Fig 4B). Taken together, these data suggest that ARQ 087 inhibits the proliferation of FGFR amplified cells by inducing G1 cell cycle arrest and apoptosis. Reference: PLoS One. 2016 Sep 14;11(9):e0162594. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023172/ |
| In vivo activity: | The in vivo anti-tumor effect of ARQ 087 was assessed in athymic mice bearing Ba/F3-FGFR2, Ba/F3-INSR, SNU-16, and NCI-H716 cell line-derived tumors. ARQ 087 demonstrated potent tumor growth inhibition in the Ba/F3-FGFR2 model, while failing to inhibit the growth of the Ba/F3-INSR model (Fig 6A and 6B). Meaningful (>50 TGI vs. control) tumor inhibition was observed both cancer cell line derived xenograft models. In the SNU-16 xenograft study, treatment with 75 mg/kg and 50 mg/kg achieved 83% (p = 0.002) and 69% (p = 0.013) TGI, respectively (Fig 6C). Partial (PR) and complete (CR) regressions also were observed in both dose groups. In the NCI-H716 human cecum model, 50 mg/kg and 75 mg/kg on a Q1Dx14 schedule demonstrated significant TGI of 68% (p = 0.0001) and 96% (p = 0.0001), respectively (Fig 6D). Reference: PLoS One. 2016 Sep 14;11(9):e0162594. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023172/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 47.7 | 101.73 | |
| DMF | 30.0 | 64.02 | |
| DMF:PBS (pH 7.2) (1:3) | 0.3 | 0.53 |
The following data is based on the product molecular weight 468.58 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, Schwartz B, Abbadessa G. Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation. PLoS One. 2016 Sep 14;11(9):e0162594. doi: 10.1371/journal.pone.0162594. PMID: 27627808; PMCID: PMC5023172. |
| In vitro protocol: | 1. Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, Schwartz B, Abbadessa G. Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation. PLoS One. 2016 Sep 14;11(9):e0162594. doi: 10.1371/journal.pone.0162594. PMID: 27627808; PMCID: PMC5023172. |
| In vivo protocol: | 1. Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, Schwartz B, Abbadessa G. Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation. PLoS One. 2016 Sep 14;11(9):e0162594. doi: 10.1371/journal.pone.0162594. PMID: 27627808; PMCID: PMC5023172. |
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5: Mazzaferro V, El-Rayes BF, Droz Dit Busset M, Cotsoglou C, Harris WP, Damjanov N, Masi G, Rimassa L, Personeni N, Braiteh F, Zagonel V, Papadopoulos KP, Hall T, Wang Y, Schwartz B, Kazakin J, Bhoori S, de Braud F, Shaib WL. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019 Jan;120(2):165-171. doi: 10.1038/s41416-018-0334-0. Epub 2018 Nov 13. PMID: 30420614; PMCID: PMC6342954.
6: El Shemerly M, Zanini E, Lecoultre M, Walker PR, Kellenberger L, Lane HA, McSheehy PMJ. Derazantinib, a fibroblast growth factor receptor inhibitor, inhibits colony-stimulating factor receptor-1 in macrophages and tumor cells and in combination with a murine programmed cell death ligand-1-antibody activates the immune environment of murine syngeneic tumor models. Anticancer Drugs. 2023 Oct 1;34(9):1035-1045. doi: 10.1097/CAD.0000000000001480. Epub 2022 Dec 19. PMID: 36729099.
7: Kotini MP, Bachmann F, Spickermann J, McSheehy PM, Affolter M. Probing the Effects of the FGFR-Inhibitor Derazantinib on Vascular Development in Zebrafish Embryos. Pharmaceuticals (Basel). 2020 Dec 30;14(1):25. doi: 10.3390/ph14010025. PMID: 33396726; PMCID: PMC7824571.
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16: Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, Schwartz B, Abbadessa G. Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation. PLoS One. 2016 Sep 14;11(9):e0162594. doi: 10.1371/journal.pone.0162594. PMID: 27627808; PMCID: PMC5023172.
17: Yu Y, Hall T, Eathiraj S, Wick MJ, Schwartz B, Abbadessa G. In-vitro and in- vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor. Anticancer Drugs. 2017 Jun;28(5):503-513. doi: 10.1097/CAD.0000000000000486. PMID: 28240679; PMCID: PMC5404396.
18: Balek L, Gudernova I, Vesela I, Hampl M, Oralova V, Kunova Bosakova M, Varecha M, Nemec P, Hall T, Abbadessa G, Hatch N, Buchtova M, Krejci P. ARQ 087 inhibits FGFR signaling and rescues aberrant cell proliferation and differentiation in experimental models of craniosynostoses and chondrodysplasias caused by activating mutations in FGFR1, FGFR2 and FGFR3. Bone. 2017 Dec;105:57-66. doi: 10.1016/j.bone.2017.08.016. Epub 2017 Aug 18. PMID: 28826843.
19: Papadopoulos KP, El-Rayes BF, Tolcher AW, Patnaik A, Rasco DW, Harvey RD, LoRusso PM, Sachdev JC, Abbadessa G, Savage RE, Hall T, Schwartz B, Wang Y, Kazakin J, Shaib WL. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br J Cancer. 2017 Nov 21;117(11):1592-1599. doi: 10.1038/bjc.2017.330. Epub 2017 Oct 3. PMID: 28972963; PMCID: PMC5729432.
