Tolinapant (dihydrochloride)

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^{[1][2][3][4][5]}. 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]. In Vivo:Tolinapant (5-20 mg/kg; p.o.; daily; 25 days; 20 mg/kg; p.o.; 7 days on/7 days off; 2 cycles) dihydrochloride significantly inhibits MDA-MB-231 breast cancer xenograft growth in SCID mice, with prolonged pharmacodynamic effects including cIAP1 degradation, XIAP antagonism, and apoptosis induction^[1].
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].