OxPhos (oxidative phosphorylation) is an energy-efficient way of synthesizing ATP in the mitochondria which is a predominant pathway in CLL (chronic lymphocytic leukemia) for energy production and is further augmented in the presence of the stromal microenvironment. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I at low nanomolar levels. Treatment of primary CLL cells with 100 nM IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In 100 nM IACS-010759-treated CLL cells, basal OCR (oxygen consumption rate, a measure of OxPhos) was greatly inhibited followed by a drastic decrease in spare respiratory capacity (after addition of FCCP, a kind of uncoupler) compared with the untreated control. CLL cells were incubated with 100 nM IACS-010759 for 24 h (n = 19) and 48 h (n = 6). The ribonucleotide pools decreased at both time points upon drug treatment. ATP concentrations in CLL cells from these patients ranged from 693 to 5267 μM with a mean of 2775 μM. This mean value decreased to 1652 μM after 24 h. At 48 h, the levels further decreased from 2124 to 943 μM. In CLL cells incubated with the combination of 100 nM IACS-010759 and 2-dG, the OCR was further and significantly reduced compared with controls and even compared with cells treated with IACS-010759 alone[1].
IACS-010759 细胞实验
Cell Line
Concentration
Treated Time
Description
References
KELLY cells
10 mM and 100 mM
24 hours
IACS-010759 significantly suppressed the oxygen consumption rate (OCR) in KELLY cells, indicating its inhibition of OXPHOS.
Cancer Res. 2021 Sep 1;81(17):4417-4430.
H1299 cells
100 nM
24-48 hours
To evaluate the growth inhibitory effect of IACS-010759 on SMARCA4 deficient cells, results showed that SMARCA4 reconstitution significantly restored cell viability.
Nat Med. 2018 Jul;24(7):1047-1057.
A549 cells
100 nM
24-48 hours
To evaluate the growth inhibitory effect of IACS-010759 on SMARCA4 deficient cells, results showed that SMARCA4 reconstitution significantly restored cell viability.
Nat Med. 2018 Jul;24(7):1047-1057.
H2030 cells
100 nM
24-48 hours
To evaluate the growth inhibitory effect of IACS-010759 on SMARCA4 deficient cells, results showed that SMARCA4 reconstitution significantly restored cell viability.
Nat Med. 2018 Jul;24(7):1047-1057.
FL5.12 cells, MYC-overexpressing B-cell lines
135 nM
48 hours
The purpose of this experiment was to assess the cytotoxic effect of IACS-010759 in MYC-overexpressing cells. The results indicated that ascorbate potentiated the pro-oxidant and antitumoral effects of IACS-010759.
EMBO Mol Med. 2023 Jun 7;15(6):e16910.
SK-N-BE(2) cells
10 mM and 100 mM
5 days
IACS-010759 significantly suppressed the growth of SK-N-BE(2) cells and induced apoptosis.
Cancer Res. 2021 Sep 1;81(17):4417-4430.
SK-N-DZ cells
10 mM and 100 mM
5 days
IACS-010759 significantly suppressed the growth of SK-N-DZ cells and induced apoptosis.
Cancer Res. 2021 Sep 1;81(17):4417-4430.
SK-N-FI cells
10 mM and 100 mM
5 days
IACS-010759 significantly suppressed the growth of SK-N-FI cells and induced apoptosis.
Cancer Res. 2021 Sep 1;81(17):4417-4430.
SK-N-SH cells
10 mM and 100 mM
5 days
IACS-010759 had a weaker inhibitory effect on the growth of SK-N-SH cells and did not significantly induce apoptosis.
Cancer Res. 2021 Sep 1;81(17):4417-4430.
THP-1 cells
5 µM
72 hours
Inhibition of complex I with IACS-010759 resulted in markedly decreased growth for cells expressing IDH1 R132H, but not for those expressing IDH2 R140Q.
Nat Commun. 2022 May 12;13(1):2614.
MCF7 LTED cells
4.7 nM
72 hours
To evaluate the sensitivity of endocrine therapy and CDK4/6 inhibitor-resistant cells to IACS-010759, results showed that MCF7 LTED cells were more sensitive to IACS-010759.
Nat Commun. 2023 Jul 14;14(1):4221.
MCF7 PalboR cells
0.6 nM
72 hours
To evaluate the sensitivity of endocrine therapy and CDK4/6 inhibitor-resistant cells to IACS-010759, results showed that MCF7 PalboR cells were more sensitive to IACS-010759.
Nat Commun. 2023 Jul 14;14(1):4221.
H460 cells
0.63, 1.25, 2.5, 5.0, 10, and 20 mM
72 hours
To evaluate the synergistic effect of IACS-010759 with trametinib, the results showed that the combination produced a strong synergy (CI <0.7) in H460 cells.
Acta Pharm Sin B. 2023 Mar;13(3):1145-1163.
Calu-1 cells
0.63, 1.25, 2.5, 5.0, 10, and 20 mM
72 hours
To evaluate the synergistic effect of IACS-010759 with trametinib, the results showed that the combination produced a strong synergy (CI <0.7) in Calu-1 cells.
Acta Pharm Sin B. 2023 Mar;13(3):1145-1163.
H441 cells
0.63, 1.25, 2.5, 5.0, 10, and 20 mM
72 hours
To evaluate the synergistic effect of IACS-010759 with trametinib, the results showed that the combination produced a strong synergy (CI <0.7) in H441 cells.
Acta Pharm Sin B. 2023 Mar;13(3):1145-1163.
T-ALL cells
0-123 nM
96 hours
IACS-010759 causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated T-ALL cells.
Nat Commun. 2022 May 19;13(1):2801.
Glioma cell lines
5 μmol/L
8-14 days
To evaluate the long-term effects of Gamitrinib on glioma cell proliferation. Results showed that Gamitrinib significantly inhibited proliferation in all glioma cell lines.
Clin Cancer Res. 2022 May 13;28(10):2180-2195.
IACS-010759 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
CD1 nude mice and NSG mice
Lymphoma xenografts
Oral Gavage and Intraperitoneal injection
1 or 2.5 mg/kg
Daily doses until tumor progression was measured
The purpose was to determine the in vivo antitumor efficacy of IACS-010759 in combination with ascorbate. The results showed significant tumor regression in the double-treated groups.
EMBO Mol Med. 2023 Jun 7;15(6):e16910.
Mice
ER+ breast cancer PDX models
Oral
10 mg/kg
5 days per week for 50 days
To evaluate the anti-tumour activity of IACS-010759 in ER+ breast cancer PDX models, results showed that IACS-010759 significantly inhibited tumour growth.
Nat Commun. 2023 Jul 14;14(1):4221.
Zebrafish
MYCN-driven neuroblastoma model
100 nmol/L
96 hours
IACS-010759 significantly suppressed the growth of MYCN-driven neuroblastoma in zebrafish models.
Cancer Res. 2021 Sep 1;81(17):4417-4430.
Mice
Notch1-mutated T-ALL model
Oral
5 mg/kg
5 days per week for 5 weeks
IACS-010759 significantly delayed leukemia progression and extended survival in a Notch1-mutated T-ALL mouse model.
Nat Commun. 2022 May 19;13(1):2801.
C57BL/6 and BALB/cA Nude mice
H460 xenograft model
Oral
5 mg/kg
Once daily for 21 days
To evaluate the inhibitory effect of IACS-010759 combined with trametinib on H460 xenograft tumors, the results showed that the combination significantly inhibited tumor growth and prolonged mouse survival.
Acta Pharm Sin B. 2023 Mar;13(3):1145-1163.
Mice
Intracranial melanoma xenograft model
Oral
5 mg/kg
Once daily for 42 days
IACS-010759 significantly improved survival in mice bearing intracranial melanoma xenografts and inhibited brain metastasis formation in the spontaneous brain metastasis model.
Cancer Discov. 2019 May;9(5):628-645
Mice
OC-PDX models
Oral
7.5 mg/kg
5 days on/2 off
To evaluate the therapeutic effects of IACS-010759 on tumor progression.
Cancer Res. 2022 Apr 1;82(7):1423-1434
Mice
KPS tumor model
Oral
7.5mg/kg
Once daily for a total of three weeks
To evaluate the in vivo anti-tumor efficacy of IACS-010759 on KPS tumors, results showed that IACS-010759 significantly inhibited the growth of KPS tumors.
Nat Med. 2018 Jul;24(7):1047-1057.
129Sv/Ev mice
PD-1 resistant and PD-1 sensitive 344SQ NSCLC adenocarcinoma xenograft models
Oral
7.5 mg/kg
Once daily until the endpoint
To evaluate the antitumor effect of IACS-010759 in combination with radiotherapy, results showed that in the PD-1 resistant model, IACS-010759 significantly inhibited tumor growth and combined therapy increased local control
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