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CAS No. 1492952-76-7
Asciminib (ABL001) is a potent and selective allosteric ABL1 inhibitor with dissociation constant (Kd) of 0.5-0.8 nM and selectivity to the myristoyl pocket of ABL1.
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Co-immunoprecipitation assays of UT7 BCR–ABL T315I (UT7 B/A T315I) cells with or without ponatinib (20 nm) or ABL001 (4 μm) treatment for 24 h. All protein extracts were immunoprecipitated with an anti-DNM2 antibody and immunoblotted with a pan-anti-p-Tyr antibody (4G10).
Leukemia, 2017, 31(11):2376-2387. Asciminib (ABL001) purchased from Selleck.
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|Description||Asciminib (ABL001) is a potent and selective allosteric ABL1 inhibitor with dissociation constant (Kd) of 0.5-0.8 nM and selectivity to the myristoyl pocket of ABL1.|
ABL001 is a potent, selective BCR-ABL inhibitor that maintains activity across most mutations, including T315I, with a distinct, allosteric mechanism of action. ABL001 binds at a regulatory site typically occupied by a myristoyl group in wild-type ABL and inhibits ABL kinase activity through a mechanism distinct from catalytic site inhibitors. It binds to a pocket on the BCR-ABL kinase domain that is normally occupied by the myristoylated N-terminus of ABL1. Upon fusion with BCR, this myristoylated N-terminus that serves to autoregulate ABL1 activity is lost. ABL001 functionally mimics the role of the myristoylated N-terminus by occupying its vacant binding site and restores the negative regulation of the kinase activity. ABL001 selectively inhibits the growth of chronic myelogenous leukemia (CML) and Ph+ ALL cells with potencies ranging from 1-10 nM range while BCR-ABL-negative cell lines remained unaffected at concentrations 1000-fold higher. NMR and biophysical studies confirm that ABL001 binds potently (dissociation constant (Kd) = 0.5-0.8 nM) and selectively to the myristoyl pocket of ABL1 and induces the inactive C-terminal helix conformation. ABL001 lacks activity against more than 60 kinases, including SRC and is similarly inactive against G-protein-coupled receptors, ion channels, nuclear receptors and transporters. Thus, ABL001 has high selectivity.
|In vivo||In the KCL-22 mouse xenograft model, ABL001 displays potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition. ABL001 has moderate oral absorption, volume of distribution and half-life across all species. It as a single agent induces clinical anti-tumour activity and is well tolerated to date in a heavily pre-treated subgroup of patients with chronic myelogenous leukemia. As for the pharmacokinetics, pharmacodynamics and efficacy of ABL001, The CL (clearance) are 12, 16 and 6 mL/min/kg in mice, rats and dogs after a sigle iv dose of 1mg/kg, 2mg/kg and 1mg/kg, respectively. In mouse and dog, the T1/2term are 1.1 and 3.7 h after a single i.v. dose at 1 mg/kg. In Rat, theT1/2term is 2.7 h after a single i.v. dose at 2 mg/kg. The oral bioavailability of ABL001 in mouse and rat are 35% and 27% respectively when dosed at 30 mg/kg p.o. While in dogs the oral BA of ABL001 is 111% (15 mg/kg, p.o).|
|In vitro||DMSO||89 mg/mL (197.84 mM)|
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Clinical Trial Information
|NCT Number||Recruitment||interventions||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT04492033||Recruiting||Drug: Paclitaxel+ ABL001|Drug: Irinotecan+ ABL001||Advanced Solid Tumors||ABL Bio Inc.|National OncoVenture||June 22 2020||Phase 1|Phase 2|
|NCT03605277||Completed||Drug: Asciminib||Renal Impairment||Novartis Pharmaceuticals|Novartis||November 16 2018||Phase 1|
|NCT03578367||Recruiting||Drug: Asciminib add-on|Drug: Imatinib|Drug: Nilotinib||CML|Chronic Myelogenous Leukemia|Leukemia Myeloid Chronic|Hematologic Diseases||Novartis Pharmaceuticals|Novartis||November 22 2018||Phase 2|
|NCT03595917||Recruiting||Drug: ABL001|Drug: Dasatinib|Drug: Prednisone||B-cell Acute Lymphoblastic Leukemia|Chronic Myeloid Leukemia (CML) in Lymphoid Blast Crisis|Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Ph+ ALL||Marlise R. Luskin|Novartis|Dana-Farber Cancer Institute||July 24 2018||Phase 1|
|NCT02857868||Completed||Drug: ABL001||Hepatic Impairment||Novartis Pharmaceuticals|Novartis||May 3 2016||Phase 1|
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