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• W4377029130 abstract "<b>Abstract ID 53328</b> <b>Poster Board 116</b> The chromosomal translocation resulting in the generation & expression of the BCR-ABL1 oncogene is a hallmark of chronic myeloid leukemia (CML). HS-10382 (TERN-701) is a potent, selective, and orally bioavailable BCR-ABL1 kinase inhibitor with IC₅₀=0.4 nM at the non-autoinhibited N-terminally truncated wild-type (WT) ABL1 protein (64-515 aa), with no significant inhibition at 375 protein kinases tested (including full-length WT ABL1). Additionally, TERN-701 is active against several BCR-ABL mutations in cells that are resistant to active site tyrosine kinase inhibitors (TKIs). In contrast to competitive type I TKIs that inhibit the transphosphorylation activity of the BCR-ABL1 oncoprotein by binding the ATP-binding site of the catalytic domain of the kinase, HS-10382 (TERN-701) targets the C-terminal myristoyl allosteric site of BCR-ABL1 to inhibit enzymatic activity, similar to asciminib. In the KCL22-s mouse subcutaneous xenograft tumor efficacy model of CML, imatinib mesylate at 75 mg/kg, flumatinib mesylate at 75 mg/kg and HS-10382 (TERN-701) at 3 mg/kg were given respectively, QD, for 15 days; positive control asciminib at 3 mg/kg and HS-10382 (TERN-701) at 1.5, 3 and 7.5 mg/kg were given, BID, for 15 days (all oral (PO) administration). The obtained tumor growth inhibition values (TGI%) were 56.03%, 193.24%, 127.26%, 87.29%, 98.20%, 187.08%, and 190.62%, respectively. The anti-tumor effect of HS-10382 (TERN-701) was higher than that of asciminib at equivalent dosing frequency and dosage (TGI% = 187.08% vs. 87.29%, <i>p</i> = 0.02). Once daily dosing at 3 mg/kg HS-10382 (TERN-701) also produced a significant anti-tumor effect compared to the twice-daily equivalent dose of asciminib. The minimum effective dose of HS-10382 (TERN-701) on the KCL22-s tumor model was 1.5 mg/kg (BID), which produced a comparable response to the positive control asciminib. Further xenograft studies using the K562 CML cell line confirmed the potency of HS-10382 (TERN-701) at the WT BCR-ABL1 kinase. Treatment with asciminib at 3 mg/kg QD or HS-10382 (TERN-701) at 1 mg/kg (QD), 3 mg/kg (QD or BID), and 10 mg/kg (QD) led to TGI values of 34.01%, 40.64%, 50.59%, 87.39%, and 120.84%, respectively. As in the KCL22-s model, treatment with HS-10382 (TERN-701) demonstrated an effective dose-response relationship with regards to tumor growth inhibition. QD treatment with 3 mg/kg HS-10382 (TERN-701) exhibited a superior anti-tumor effect (<i>p</i> = 0.04) over QD treatment with 3 mg/kg asciminib (<i>p</i> = 0.17) relative to the vehicle control. The BCR-ABL1 T315I mutant is resistant to several approved competitive TKIs in the clinic. In the Ba/F3 BCR-ABL1-T315I model, flumatinib mesylate at 75 mg/kg, asciminib at 50 mg/kg, and HS-10382 (TERN-701) at 25, 50, and 75 mg/kg were dosed BID for 14 days (all PO administration); the corresponding tumor growth inhibition values (TGI%) were 20.25%, 9.33%, 23.28%, 51.80%, and 48.69%, respectively. The anti-tumor effect of HS-10382 (TERN-701) was greater than that of asciminib (TGI%=51.80% vs. 9.33%, <i>p</i> = 0.0004) at the equivalent dose and dosing frequency. The minimum effective dose of HS-10382 (TERN-701) in the Ba/F3 BCR-ABL1-T315I model was 50 mg/kg (BID). The anti-tumor effects of HS-10382 (TERN-701) in mouse xenograft models of human CML indicate that the molecule is a potent inhibitor of tumor growth with potential for efficacious once-daily dosing. HS-10382 (TERN-701) holds promise of translation to treatment of human CML." @default.
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• W4377029130 date "2023-05-18" @default.
• W4377029130 modified "2023-09-29" @default.
• W4377029130 title "Efficacy of HS-10382 (TERN-701) in tumor xenograft models, a new investigational allosteric ABL1 kinase inhibitor as a potential treatment for CML" @default.
• W4377029130 doi "https://doi.org/10.1124/jpet.122.533280" @default.
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