Eltanexor targets exportin-1 (XPO1), also known as chromosome region maintenance 1 (CRM1), a nuclear export receptor responsible for transporting tumor suppressor proteins and growth regulators from the nucleus to the cytoplasm. As a SINE compound, it covalently binds to XPO1 at Cys528, blocking the nuclear export of key proteins such as p53, p21, and p27. This restores the nuclear localization and function of tumor suppressing proteins, leading to the induction of apoptosis in tumor cells.

KPT-8602 (15 mg/kg; oral gavage; daily for 12 days) demonstrates strong anti-lymphoblastic leukemia efficacy[1].
In vitro, Eltanexor inhibits viability of human AML cell lines with IC50 values of 20-211 nM after 3 days exposure, showing greater activity than the first-generation XPO1 inhibitor selinexor. It inhibits XPO1-dependent nuclear export with an EC50 of 60.9 nM. Eltanexor induces Caspase-dependent apoptosis in a panel of leukemic cell lines. It also inhibits human cytomegalovirus (CMV) replication in primary human foreskin fibroblasts with an IC50 of 37.62 nM. At a concentration of 10 µM, it inhibits the binding of XPO1/CRM1 to various nuclear export signals (NESs) in cell-free pull-down assays.

KPT-8602 (15 mg/kg; daily dose; cavity feeding; 12 days) shows strong antioxidant bleaching activity [1].
In vivo, Eltanexor is orally bioavailable with similar pharmacokinetic properties to selinexor but exhibits markedly reduced (approximately 30-fold less) penetration across the blood-brain barrier. In mouse models, it has demonstrated potent anti-leukemic activity and nearly complete elimination of human AML cells in the AML-CN model. It also improved dystrophic skeletal muscle pathologies in zebrafish and mouse models of Duchenne muscular dystrophy. Eltanexor has shown minimal toxicity and synergistic cell activity in vivo.

In vitro enzyme/receptor binding assays for Eltanexor typically measure binding to XPO1/CRM1 using cell-free pull-down assays with nuclear export signal (NES)-conjugated beads. Alternatively, cellular nuclear export assays use reporter constructs (e.g., GFP-NES fusion proteins) to monitor CRM1-dependent nuclear export. Cells are treated with various concentrations of Eltanexor, and nuclear versus cytoplasmic fluorescence is quantified by microscopy or plate reader. EC50 for inhibition of nuclear export is calculated from dose-response curves.

Cell viability assay[1]
Cell Types: T-ALL cells (Jurkat, MOLT-4 , ALL-SIL, DND41 and HPB-ALL), B-ALL cells (BV173, EHEB and REH), AML cells (MV4-11, MOLM13, K-562 and HL-60)
Tested Concentrations: 2, 4, 6 nM
Incubation Duration: 72 hrs (hours)
Experimental Results: diminished cell viability with EC50 values ranging from 25 to 145 nM.

---

Western Blot Analysis[1]
Cell Types: T-ALL, B-ALL, AML Cell
Tested Concentrations: 1 μM
Incubation Duration: 16
Experimental Results: Earliest 6 Cleaved caspase-3 substrate PARP appears within hrs (hours).
For in vitro cellular assays, human AML cell lines and other cancer cell lines are cultured and treated with various concentrations of Eltanexor for 16-72 hours. Cell viability is measured using MTT, CellTiter-Glo, or similar assays. Apoptosis is assessed by caspase-3/7 activity, Annexin V staining, or PARP cleavage analysis by Western blotting. Nuclear export of cargo proteins is assessed by immunofluorescence or subcellular fractionation. These assays confirm the compound's potent anti-leukemic activity and its mechanism of action.

Animal/Disease Models: Female balb/c (Bagg ALBino) mouse (model using JAK3 (M511I) mutation) [1]
Doses: 15 mg/kg
Route of Administration: po (oral gavage); one time/day for 12 days
Experimental Results: Comparable to placebo-treated animals After 2 days of treatment, the total white blood cell (WBC) count was Dramatically diminished, and the WBC count continued to decrease until reaching normal levels (<10,000 cells/μL) on day 12.
In vivo animal studies for Eltanexor utilize mouse xenograft models of AML, acute lymphoblastic leukemia (ALL), and other hematological malignancies. The compound is administered orally at various doses (e.g., 15 mg/kg daily for 12 days in BALB/c mice). Tumor volume is measured over time, and survival is monitored. Pharmacodynamic endpoints include assessment of nuclear export inhibition in tumor tissue and apoptosis markers. Efficacy is compared to vehicle and reference SINE (selinexor).

Eltanexor is orally bioavailable with favorable pharmacokinetic properties. In humans, it is absorbed with a Tmax of approximately 2 hours. The compound has similar pharmacokinetic properties to selinexor but exhibits markedly reduced (approximately 30-fold less) penetration across the blood-brain barrier, which may reduce central nervous system-related side effects. The pharmacokinetic and pharmacodynamic (XPO1 mRNA) profiles have been evaluated in clinical studies.

Preclinical and clinical toxicity of Eltanexor shows a favorable safety profile. As a second-generation SINE, it has reduced brain penetration, potentially reducing CNS side effects such as fatigue, nausea, and anorexia that are associated with selinexor. In Phase 1/2 trials, it has demonstrated an acceptable toxicity profile. Hazard classifications indicate it is toxic if swallowed, irritating to skin, and carries a risk of serious damage to eyes. Standard toxicology studies have been conducted to support clinical development.

[1]. The second-generation exportin-1 inhibitor KPT-8602 demonstrates potent activity against acute lymphoblastic leukemia. Clin Cancer Res. 2016 Oct 25.

Eltanexor is a triazole compound with the structure 1H-1,2,4-triazole, substituted at positions 1 and 3 by (1E)-3-amino-3-oxo-2-(pyrimidin-5-yl)prop-1-en-1-yl and 3,5-bis(trifluoromethyl)phenyl, respectively. It is a second-generation export protein 1 inhibitor currently undergoing a phase II clinical trial for the treatment of patients with relapsed/refractory myelodysplastic syndromes. It exhibits a triple action of inhibiting export protein 1, antitumor activity, and inducing apoptosis. It belongs to the (trifluoromethyl)benzene, triazole, pyrimidine, enamide, and primary carboxamide classes. Eltanexor is being investigated in the clinical trial NCT02649790 (KPT-8602: Safety, Tolerability, and Efficacy Study in Patients with Relapsed/Refractory Cancer). Eltanexor is an orally bioavailable export protein-1 (XPO1; a homolog of chromosomal region maintenance protein 1; CRM1) inhibitor with potential antitumor activity. Upon administration, eltanexor binds to the cargo binding site of XPO1, thereby preventing XPO1-mediated nuclear export of cargo proteins (such as tumor suppressor proteins (TSPs), including p53, p73, BRCA1/2, pRB, FOXO, and other growth regulators), leading to the selective accumulation of these cargo proteins within the tumor cell nucleus. As a selective nuclear export inhibitor (SINE), KPT-8602 restores the nuclear localization and function of tumor suppressor proteins, thereby inducing tumor cell apoptosis. XPO1 is a major protein export factor responsible for transporting proteins from the nucleus to the cytoplasm. XPO1 is overexpressed in a variety of cancer cells, but expressed at extremely low levels in normal healthy cells. The export of tumor suppressor proteins to the cytoplasm prevents them from initiating apoptosis, leading to uncontrolled proliferation of tumor cells.
Eltanexor (KPT-8602, ONO-7706, ATG-016) is a second-generation, orally bioavailable SINE compound targeting XPO1/CRM1. It is currently in Phase 1/2 clinical trials for relapsed/refractory cancers including AML, MDS, and multiple myeloma. It has received FDA Fast Track status and Orphan Medicinal Product designation in Europe for MDS. Eltanexor demonstrates fewer adverse effects than its precursors and shows synergistic activity with other agents such as venetoclax and dexamethasone. It is available for research purposes only.

C17H10F6N6O

428.2984

428.082

1642300-52-4

Eltanexor Z-isomer;1642300-78-4

86345880

Off-white to light yellow solid powder

1.6±0.1 g/cm3

574.4±60.0 °C at 760 mmHg

301.2±32.9 °C

0.0±1.6 mmHg at 25°C

1.594

2.83

1

11

4

30

626

0

C1=C(C=C(C=C1C(F)(F)F)C(F)(F)F)C2=NN(C=N2)/C=C(\C3=CN=CN=C3)/C(=O)N

JFBAVWVBLRIWHM-AWNIVKPZSA-N

InChI=1S/C17H10F6N6O/c18-16(19,20)11-1-9(2-12(3-11)17(21,22)23)15-27-8-29(28-15)6-13(14(24)30)10-4-25-7-26-5-10/h1-8H,(H2,24,30)/b13-6+

(E)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-2-pyrimidin-5-ylprop-2-enamide

KPT-8602 KPT8602 KPT 8602. Eltanexor.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~233.49 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: 2.5 mg/mL (5.84 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)