부산대학교 도서관

Context Although tyrosine kinase inhibitors (TKIs) targeting the ATP-binding site of the BCR::ABL1 oncoprotein are effective therapeutics for chronic myeloid leukemia (CML), patients often develop drug resistance due to ATP-site mutations that inhibit drug binding. TERN-701/HS-10382 acts allosterically to Specifically Target the ABL Myristoyl Pocket (STAMP) of BCR::ABL1, resulting in its inhibition. TERN-701/HS-10382 is designed to circumvent the resistance of active site mutations, with the potential for synergistic combinations with active site TKIs.Objective To characterize the potency, selectivity, and ability of TERN-701/HS-10382 to work synergistically with active site TKIs.Methods Substrate phosphorylation assays were used to assess the effect of TERN-701/HS-10382 on BCR::ABL1 and other kinases. The ability of TERN-701/HS-10382 to inhibit the proliferation of wild-type and mutant CML cell lines was assessed using CellTiter-Glo®. Synergy between TERN-701/HS-10382 and active site TKIs was assessed using both fixed molar combinations and expanded combination matrices, with interactions quantified using the Bliss, HSA, and Loewe models.Results TERN-701/HS-10382 inhibited native BCR::ABL1 in in vitro biochemical assays with an IC50 = 0.4 nM and inhibited cell proliferation in native and mutant cell lines with IC50s of 0.6 – 34.7 nM, depending on genetic background and BCR::ABL1 mutation status. TERN-701/HS-10382 retained activity against the clinically relevant T315I mutation. With respect to selectivity, in an in vitro kinase panel, TERN-701/HS-10382 did not inhibit any kinase by >50% at 1 μM, including full-length ABL1. TERN-701/HS-10382 was highly potent and selective against only BCR::ABL1+ cell lines in cancer cell line panel and was more selective than asciminib. In vitro combination studies revealed that TERN-701/HS-10382 works synergistically with multiple TKIs in the K562 cell line and additively in the Ku812 line.Conclusions TERN-701/HS-10382 is a potent and selective allosteric inhibitor of BCR::ABL1 in cellfree and cell-based assays and screens, with comparable potency and synergy profiles to that of asciminib while potentially being more selective. TERN-701/HS-10382 retains activity against the T315I gatekeeper mutation, which confers resistance to all approved active site TKIs except for ponatinib, which has known safety liabilities. These data support the continued development of TERN-701/HS-10382 for the treatment of CML.