Tipifarnib

Catalog No.S1453 Batch:S145307

Technical Data

Formula	C₂₇H₂₂Cl₂N₄O
Molecular Weight	489.4	CAS No.	192185-72-1
Solubility (25°C)*	In vitro	DMSO	12 mg/mL (24.51 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

Tipifarnib is a potent and specific farnesyltransferase (FTase) inhibitor with IC50 of 0.6 nM, its anti-proliferative effects are most prominent in H-ras or N-ras mutant cells. Phase 3.

Targets

FTase ^[1]

0.6 nM

In vitro

Using Tipifarnib 5 μM for 72 hours, the percentage of apoptotic cells is significantly higher in drug-treated compared to DMSO-treated LGL T-cells. Using T-cells from healthy donors, Tipifarnib reduces the percentage of IFNγ-positive cells in a time-dependent manner. Tipifarnib reduces the amount of activated Ras in precipitates compared to DMSO. ^[2] Tipifarnib exerts selective in vitro toxicity against clonal MDS hematopoiesis at concentrations less than 10 nM the effect being more prominent in white cell progenitors. This action is not due to apoptosis induction as both normal and MDS progenitors displays equivalent DiOC3 and annexin V expression up to 72 hours after exposure to Tipifarnib. ^[3] Combining Tipifarnib with 10 nM 4-OH-tamoxifen in the presence of E2 reduces the IC50 8-fold from 400 to 50 nM. ^[4] Tipifarnib induces apoptosis in U937 cells. ^[5] In addition, Tipifarnib inhibits isolated human farnesyltransferase for a lamin B peptide and for the K-RasB peptide with IC50 of 0.86 nM and 7.9 nM, respectively. ^[6]

In vivo

Ki-67 is lower in the tumors treated with E2 withdrawal plus R115777 compared with E2 withdrawal alone. The combination of tamoxifen and R115777 results in significantly lower Ki-67 compared with either tamoxifen or R115777 alone (mean of 5% versus 16.9% and 67.3%, respectively). ^[4] In contrast, no significant difference in apoptotic scores is seen between the treatment groups. R115777 alone also reduces the CTI compared with control. The combination of tamoxifen and R115777 or R115777 coupled with E2 withdrawal is most effective at lowering the CTI (0.8 and 0.7, respectively), which may account for the decrease in tumor volume. ^[4]

Features

A potent and selective farnesyl protein transferase inhibitor with significant antitumor effects.

Protocol (from reference)

Cell Assay:^{^[4]}	Cell lines MACS-selected CD34+ cells Concentrations 2.5 nM, 10 nM, 25 nM and 50 nM Incubation Time 48 hours Method MACS-selected CD34+ cells are seeded in Methocult 4435 'complete' 1% bovine serum albumin, 3 U/mL recombinant human (rh) erythropoietin, 0.1 mM 2-mercaptoethanol, 2 mM L-glutamine and the following cytokines: 50 ng/mL rh stem cell factor, 20 ng/mL rh GM-CSF, 20 ng/mL rh IL-3, 20 ng/mL rh IL-6 and 20 ng/mL h G-CSF. DMSO or Tipifarnib is added at the concentrations of 2.5, 10, 25 and 50 nM at day 1. All cultures are performed in duplicates and the numbers of colonies are scored after 14 days of incubation at 37 °C in a humidified incubator containing 5% CO₂
Animal Study:^{^[4]}	Animal Models Female ovariectomized Ncr foxhead nude mice Dosages 50 mg/kg Administration Oral gavage

Cell Assay:^{^[4]}

Cell lines
MACS-selected CD34+ cells
Concentrations
2.5 nM, 10 nM, 25 nM and 50 nM
Incubation Time
48 hours
Method
MACS-selected CD34+ cells are seeded in Methocult 4435 'complete' 1% bovine serum albumin, 3 U/mL recombinant human (rh) erythropoietin, 0.1 mM 2-mercaptoethanol, 2 mM L-glutamine and the following cytokines: 50 ng/mL rh stem cell factor, 20 ng/mL rh GM-CSF, 20 ng/mL rh IL-3, 20 ng/mL rh IL-6 and 20 ng/mL h G-CSF. DMSO or Tipifarnib is added at the concentrations of 2.5, 10, 25 and 50 nM at day 1. All cultures are performed in duplicates and the numbers of colonies are scored after 14 days of incubation at 37 °C in a humidified incubator containing 5% CO₂

Animal Study:^{^[4]}

Animal Models
Female ovariectomized Ncr foxhead nude mice
Dosages
50 mg/kg
Administration
Oral gavage

References

+ Expand

Customer Product Validation

: Data from [Data independently produced by Shock, 2014, 42(6), 570-7]

: Data from [Data independently produced by Leuk Res, 2014, 10.1016/j.leukres.2014.09.002]

: Data from [Data independently produced by J Clin Endocrinol Metab, 2013, 98(6), 2502-12]

: Data independently produced by , , Dr. Milica Pesic from Institute for Biological Research

Selleck's Tipifarnib has been cited by 36 publications

Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment [ Cell Rep, 2023, 42(9):113098]	PubMed: 37714156
Salivary gland cancer organoids are valid for preclinical genotype-oriented medical precision trials [ iScience, 2023, 26(5):106695]	PubMed: 37207275
Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression [ Int J Mol Sci, 2023, 24(14)11546]	PubMed: 37511305
Cooperative Genomic Lesions in HRAS-Mutant Cancers Predict Resistance to Farnesyltransferase Inhibitors [ Res Sq, 2023, rs.3.rs-3154719]	PubMed: 37503077
BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy [ Nat Commun, 2022, 13(1):7113]	PubMed: 36402789
Impact of a conserved N-terminal proline-rich region of the α-subunit of CAAX-prenyltransferases on their enzyme properties [ Cell Commun Signal, 2022, 20(1):118]	PubMed: 35941619
Combination of Tipifarnib and Sunitinib Overcomes Renal Cell Carcinoma Resistance to Tyrosine Kinase Inhibitors via Tumor-Derived Exosome and T Cell Modulation [ Cancers (Basel), 2022, 14(4)903]	PubMed: 35205655
Bacteria Are New Targets for Inhibitors of Human Farnesyltransferase [ Front Microbiol, 2021, 12:628283]	PubMed: 34917041
The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A. [ Int Immunopharmacol, 2020, 3;83:106462]	PubMed: 32251961
Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras. [ Cell, 2019, 36(2):179-193]	PubMed: 28162770

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SHIPPING AND STORAGE
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