Tolinapant dihydrochloride
Based on 4 publication(s) in Google Scholar
Tolinapant dihydrochloride (ASTX660 dihydrochloride) is an orally active cIAP1/2 and XIAP antagonist, with an IC50 of < 40 nM against XIAP and an IC50 of <12 nM against cIAP1. Tolinapant dihydrochloride triggers TNFα-dependent Apoptosis in cancer cells. Tolinapant dihydrochloride inhibits tumor growth in mouse xenograft models. Tolinapant dihydrochloride can be used in research related to breast cancer, melanoma, lymphoma, multiple myeloma, acute lymphoblastic leukemia and advanced solid tumors.
For research use only. We do not sell to patients.
- CAS No.: 1799328-50-9
- Formula: C30H44Cl2FN5O3
- Molecular Weight:612.61
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Purity & Documentation
- References
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Publications Citing Use of MedChemExpress (MCE) Tolinapant dihydrochloride
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Biological Activity
Description
IC50 & Target
[1]|
cIAP1 <12 nM (IC50) |
cIAP2 |
XIAP ＜40 nM (IC50) |
In Vitro
Tolinapant dihydrochloride potently inhibits the binding of SMAC peptides to purified XIAP-BIR3 (IC50 <40 nM) and cIAP1-BIR3 (IC50 <12 nM) proteins by occupying the endogenous SMAC-binding pocket[1].
Tolinapant (0.001-10 μM; 5 min-16 h) dihydrochloride antagonizes endogenous XIAP in A375 melanoma cells, and displaces SMAC from XIAP at concentrations above 0.01 μM after 16 h, or within 5 min at a concentration of 1 μM[1].
Tolinapant (72 h) dihydrochloride inhibits the viability of most melanoma cell lines, with enhanced activity in the presence of TNFα, and exerts no significant effect on the viability of normal skin fibroblasts[1].
Tolinapant dihydrochloride exhibits single-agent or TNFα-potentiated anti-survival activity in 43% of the tested triple-negative breast cancer (TNBC) cell lines, including MDA-MB-231, HCC38, HCC1806, Hs578T, BT549, HCC1395, DU4475, MDA-MB-453, and the mouse EMT6 cell line[3].
Tolinapant (1-3 μM; 24 h) dihydrochloride significantly enhances the lytic activity of NY-ESO-1 TCR-T cells against A375 melanoma cells, and this effect is dependent on TNF-α[4].
Tolinapant (0.01-1 μM; 48 h) dihydrochloride significantly enhances CD19 CAR-NK cell-mediated lysis of NALM6-Luc2 cells in a TNF-α-dependent manner[4].
Tolinapant (3 μM; for at least 33 days) dihydrochloride enhances the long-term proliferation and persistence of CD19 CAR-T cells, maintains their cytotoxic activity, and preserves the expression of the memory T cell marker CCR7 during repeated antigen stimulation[4].
Tolinapant dihydrochloride inhibits the proliferation of various cancer cell lines in a manner dependent on the presence of inflammatory stimulation[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:A375 human melanoma cells
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Concentration:0.001-10 μmol/L (16 h incubation); 1 μmol/L (short-term incubation)
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Incubation Time:16 h (0.001-10 μmol/L); 5-240 min (1 μmol/L)
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Result:Reduced SMAC levels immunoprecipitated with XIAP at concentrations above 0.01 μmol/L after 16 hours of treatment.
Antagonized the interaction of SMAC with XIAP within 5 minutes of exposure to 1 μmol/L.
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Cell Line:human CD19 CAR-T cells, NALM6-Luc2 (B-ALL)
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Concentration:3 μM
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Incubation Time:at least 33 days
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Result:Increased CD19 CAR-T cell growth rate relative to DMSO control, with CAR-T cells persisting for at least 33 days (compared to decline by Day 18 in controls).
Maintained specific lysis of NALM6-Luc2 cells at consistently high 80-90% throughout the study period.
Preserved expression of the memory T cell marker CCR7.
In Vivo
Tolinapant (10-20 mg/kg; p.o.; daily; 14 days) dihydrochloride significantly inhibits A375 melanoma xenograft growth in nude mice[1].
Tolinapant (30-100 mg/kg; p.o.; daily; 7-14 days) dihydrochloride achieves complete on-target engagement via full cIAP1 protein degradation in cynomolgus NHP PBMCs[2].
Tolinapant (16 mg/kg; p.o.; once daily; 21 days) dihydrochloride enhances the in vivo anti-tumor efficacy of low-dose MMG49 CAR-T cells in a disseminated multiple myeloma xenograft model by accelerating CAR-T cell proliferation and persistence, enabling tumor control equivalent to a 10-fold higher dose of CAR-T cells alone[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/cJHanHsd-Prkdcscid (male)[1]
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Dosage:5 mg/kg; 10 mg/kg; 20 mg/kg; 20 mg/kg (intermittent schedule)
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Administration:p.o.; daily; 25 days; p.o.; 7 days on/7 days off; 2 cycles
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Result:Significantly inhibited tumor growth (P < 0.05 from days 15, 18, and 11 for 5, 10, and 20 mg/kg daily dosing, respectively).
Achieved significant tumor growth inhibition (P < 0.05 vs. vehicle from day 8) with intermittent 20 mg/kg schedule, equivalent to continuous 20 mg/kg daily schedule.
Distributed to tumors with detectable compound levels up to 168 hours post-dose (AUC_last = 129 μmol/L/h/mL).
Induced rapid cIAP1 degradation, reduced XIAP:SMAC association (persisting up to 3 days), and increased cleaved PARP and cleaved caspase-3 within 1 hour post-dose.
Showed no excessive body weight loss or adverse effects.
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Animal Model:BALB/cOlaHsd-Foxn1nu (male)[1]
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Dosage:10 mg/kg; 20 mg/kg
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Administration:p.o.; daily; 14 days
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Result:Caused significant tumor growth inhibition (P < 0.05 from day 8).
Showed no excessive body weight loss or adverse effects.
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Animal Model:NOD/SCID/IL2Rγcnull (NOG) (6- to 8-week-old female; disseminated multiple myeloma xenograft model)[4]
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Dosage:16 mg/kg
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Administration:p.o.; once daily; 21 days
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Result:Attenuated tumor expansion by day 11 and reduced tumor load thereafter when combined with 1×105 MMG49 CAR-T cells, resulting in lower tumor load than treatment with 1×106 MMG49 CAR-T cells alone by day 21.
Accelerated in vivo MMG49 CAR-T cell expansion, with significantly higher CAR-T cell numbers in the combination group than in the CAR-T monotherapy group between days 10 and 17.
Showed no anti-tumor effect when used alone.
Chemical Information
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CAS No. 1799328-50-9
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Molecular Weight 612.61
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Formula C30H44Cl2FN5O3
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SMILES
C[C@H](COCC1)N1C[C@@H](CN[C@H](C)C2)N2CC(N3C4=CC(CC5=CC=C(F)C=C5)=C(CO)N=C4C(C)(C)C3)=O.Cl.Cl
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Synonyms
ASTX660 dihydrochloride
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Publications (4)
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Journal Impact Factor
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Most Recent
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Cell Rep Med
Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo. [Abstract]2020 Jun 23;1(3):100037. PMID: 33205060 -
Cancer Gene Ther
b-AP15 enhances TRAIL-induced cell death in HNSCC via the induction of ROS/JNK/DR5 signalling. [Abstract]2026 May 2. PMID: 42069980 -
Blood Res
Translational investigation of tolinapant (ASTX660) in acute myeloid leukemia by integrating clinical, bioinformatic and pharmacological approaches. [Abstract]2025 Dec 30;60(1):67. PMID: 41469824 -
bioRxiv
2024 Nov 28:2024.11.25.625306. PMID: 39651304
Purity & Documentation
References
[1]. Ward GA, et al. ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth. Molecular cancer therapeutics. 2018 Jul;17(7):1381-1391. [Content Brief]
[2]. Martins V, et al. The preclinical pharmacokinetics of Tolinapant-A dual cIAP1/XIAP antagonist with in vivo efficacy. Pharmacology research & perspectives. 2024 Dec;12(6):e70030. [Content Brief]
[4]. Tazuru K, et al. The IAP antagonist tolinapant enhances the anti-tumor activity of cell therapies. European journal of pharmacology. 2025 May 15;995:177400. [Content Brief]
[5]. Mita MM, et al. A Phase I Study of ASTX660, an Antagonist of Inhibitors of Apoptosis Proteins, in Adults with Advanced Cancers or Lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Jun 15;26(12):2819-2826. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Tolinapant dihydrochloride Related Classifications
HY-109565B Related Classifications
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