Batoprotafib (TNO155) is a highly potent, selective, and orally active allosteric inhibitor of wild-type SHP2, with an IC50 of 0.011 µM. It holds promise for investigating RTK-dependent malignancies, particularly advanced solid tumors [1].
体内研究
The oral bioavailability in mouse, rat, and monkey is 78%, 86%, and 60%, respectively [1].
Batoprotafib (20 mg/kg; oral administration; twice daily for 40 days) suppresses tumor growth and exhibits enhanced efficacy when administered in combination with Dabrafenib plus Trametinib in nude mice harboring HT-29 xenografts [2].
Batoprotafib (7.5 mg/kg; pO.; b.iD. or qD. for 36 days) in combination with JDQ-443 (100 mg/kg; pO.; qD.) enhances the efficacy of JDQ443 alone in KRASG12C-mutated cell-derived (CDX) models in nude mice [3].
体外研究
Batoprotafib exhibits an IC50 of 0.008 μM in the KYSE520 pERK assay and a 0.100 μM IC50 in the KYSE520 5-day cell proliferation assay. Off-target IC50 values are 18 μM, 6.9 μM, and 11 μM for Cav1.2, VMAT, and SST3, respectively [1].
Batoprotafib (0-1000 nM; 6 days) demonstrates inhibition of NCI-H3255, HCC827, and PC9 cell viability with IC50 values below 1.5 μM. It exhibits efficacy in EGFR-mutant NSCLC cell lines [2].
Batoprotafib is effective in acquired resistance models of EGFR inhibitors and shows synergistic effects when combined with EGFR inhibitors [2].
Batoprotafib improves the effectiveness of KRASG12C inhibitors in treating KRASG12C lung and colorectal cancers [2].
Batoprotafib suppresses immune-suppressive macrophages and enhances the effects of PD1 blockade [2].
Batoprotafib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
OSCC cell lines
3 μM
72 hours
To evaluate the inhibitory effect of TNO155 on OSCC cell lines, results showed that TNO155 exhibited high efficacy in most OSCC cell lines, with IC50 ranging from 0.39 μM to 211.1 μM.
Heliyon. 2024 Oct 22;10(21):e39677.
JH-2-002
0.3 μM
48 hours
To evaluate the effect of TNO155 on cell cycle and apoptosis-related proteins, results showed that TNO155 significantly inhibited cell cycle regulators and inhibitor-of-apoptosis proteins.
Sci Adv. 2023 Nov 24;9(47):eadg8876.
ST8814
30-3000 nM
24 hours
To evaluate the effect of TNO155 on ERK signaling pathway and cell cycle regulators, results showed that TNO155 dose-dependently inhibited ERK signaling pathway and cell cycle regulators.
Sci Adv. 2023 Nov 24;9(47):eadg8876.
Kelly
2.5±1.7 μmol/L
72 hours
Evaluate the sensitivity of ALK-mutant neuroblastoma cells to TNO155, results showed ALK-mutant cells were more sensitive to TNO155
Cancer Res Commun. 2023 Dec 27;3(12):2608-2622.
LAN-6
1.1±0.4 μmol/L
72 hours
Evaluate the sensitivity of ALK-mutant neuroblastoma cells to TNO155, results showed ALK-mutant cells were more sensitive to TNO155
Cancer Res Commun. 2023 Dec 27;3(12):2608-2622.
SK-N-SH
0.6±0.2 μmol/L
72 hours
Evaluate the sensitivity of ALK-mutant neuroblastoma cells to TNO155, results showed ALK-mutant cells were more sensitive to TNO155
Cancer Res Commun. 2023 Dec 27;3(12):2608-2622.
AZDR14 cells
1 µM
24 hours
TNO155 inhibited GAB1 phosphorylation and disrupted the association between SHP2 and GAB1, thereby inhibiting the ERK1/2 signaling pathway
Cells. 2022 Jul 14;11(14):2201.
Batoprotafib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
KRASG12C-mutated MIA PaCa-2 pancreatic and NCI-H2122 lung cancer cell-derived xenograft models
Oral
10 mg/kg
Once or twice daily until the end of the experiment
To evaluate the antitumor activity of JDQ443 in KRASG12C-mutated tumor models, results showed dose-dependent inhibition of tumor growth.
Cancer Discov. 2022 Jun 2;12(6):1500-1517.
NRG mice
MPNST PDX model
Oral gavage
7.5 mg/kg
TNO155 twice daily, ribociclib once daily, for 4 weeks
To evaluate the effect of TNO155 alone or in combination with ribociclib on tumor growth in MPNST PDX models, results showed that TNO155 alone exhibited significant antitumor activity in some models, while the combination showed deeper antitumor effects in partially sensitive models.
Sci Adv. 2023 Nov 24;9(47):eadg8876.
Mouse
LU99 (KRASG12C NSCLC) xenograft model
Oral
10 mg/kg BID
Twice daily for 21 days
Evaluate the effect of TNO155 alone and in combination with JDQ443 on LU99 tumor growth, showing combination treatment significantly extended the duration of tumor responses.
Cancer Res. 2023 Dec 15;83(24):4130-4141.
Zebrafish
Neuroblastoma xenograft model
Dissolved in water
5 or 10 μmol/L
72 hours
Evaluate the antitumor activity of TNO155 alone or in combination with ALK-TKIs in neuroblastoma xenografts, results showed combination treatments significantly reduced tumor growth
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