Molecular Formula | C20H18ClF2N5O3 |
Molar Mass | 449.84 |
Solubility | DMSO |
Storage Condition | -20℃ |
Physical and Chemical Properties | Bioactive Asciminib (ABL001) is an effective and selective ABL1 allosteric inhibitor with a Kd value of 0.5-0.8 nM, which binds to the tetradecyl pocket of ABL1. |
In vitro study | ABL001 is a potent, selective BCR-ABL inhibitor that is active against most mutant forms, such as T315I. Binding of ABL001 to the regulatory site of ABL1, which in wild-type ABL is usually occupied by a myristoyl group. ABL001 inhibits ABL kinase activity by an inhibitor mechanism that is different from other targeted catalytic sites. It binds to the pocket of the BCR-ABL kinase region, which, under normal conditions, is occupied by the N-terminal ten-alkyl of ABL1, and once bound to BCR, N-terminal loss of eighteen alkylations acting on the ABL 1 self-regulating function. By binding to this blank site, ABL001 mimics the effect of the N-terminal of the eighteen alkyl group, thereby restoring the negative regulatory function of the kinase activity. ABL001 at concentrations of 1-10 nM selectively inhibited the growth of CML and Ph ALL cells; Whereas BCR-ABL-negative cells were unaffected by ABL001 even at concentrations as high as 1000-fold or more. The dissociation constant Kd for the binding of ABL001 to The myristoyl pocket of ABL is 0.5-0.8 nM, inducing an inactivated C- terminal helical conformation. ABL001 was not active on more than 60 kinases tested, including SRC, nor on G protein-coupled receptors, ion channels, nuclear receptors, and transporters. Thus ABL001 has high selectivity. |
In vivo study | In a KCL-22 mouse xenograft model, ABL001 has potent anti-tumor activity, can cause complete tumor regression, and has a concentration-dependent relationship with the inhibitory effect of pstat5. ABL001 has moderate oral absorption, in vivo volume distribution, and half-life. When administered as a single agent, it can induce clinical anti-tumor activity and is well tolerated in CML (chronic myeloid leukemia) patients who have received multiple chemotherapies. For its pharmacokinetics, pharmacodynamics, in mice, rats and dogs in a single intravenous injection of 1 mg/kg, 2 mg/kg and 1 mg/kg of ABL001, plasma clearance (CL) 12, 16 and 6 mL/min/kg, respectively. In mice and dogs, T 1/2term was 1.1 and 3.7 hours, respectively, with a single intravenous injection of 1 mg/kg ABL001. In rats, a single intravenous injection of 2 mg/kg,T 1/2term for 2.7 hours. After oral administration of 30 mg/kg ABL001 to mice and rats, the oral bioavailability was 35% and 27%, respectively; While in dogs, oral administration of 15 mg/kg ABL001, the oral bioavailability was 111%. |
1mg | 5mg | 10mg | |
---|---|---|---|
1 mM | 2.223 ml | 11.115 ml | 22.23 ml |
5 mM | 0.445 ml | 2.223 ml | 4.446 ml |
10 mM | 0.222 ml | 1.112 ml | 2.223 ml |
5 mM | 0.044 ml | 0.222 ml | 0.445 ml |
Target
Target Value
Abl1
(Cell-free assay) 0.45 nM
in vitro studies
ABL001 is an effective and selective BCR-ABL inhibitor with activity against most mutants, such as T315I. ABL001 binds to the regulatory site of ABL1. In wild-type ABL, this site is usually occupied by a myristoyl group. ABL001 inhibits ABL kinase activity through an inhibitor mechanism different from other targeting catalytic sites. It binds to the pocket of the BCR-ABL kinase region. Under normal conditions, this region is occupied by the decylated N-terminal of ABL1. Once combined with BCR, the decylated N-terminal acting on the self-regulation function of ABL1 is lost. By binding to this blank site, ABL001 simulates the effect of the N-terminal decylated, thus restoring the negative regulatory function of kinase activity. ABL001 at a concentration of 1-10 nM can selectively inhibit the growth of CML and Ph + ALL cells. Even when the concentration is as high as 1000 times higher, BCR-ABL-negative cells are not affected by ABL001. The dissociation constant Kd for ABL001 binding to the myristoyl pocket of ABL is 0.5-0.8 nM, inducing an inactivated C- terminal helix conformation. ABL001 has no activity on more than 60 kinases detected, including SRC. At the same time, it has no activity on G protein coupled receptors, ion channels, nuclear receptors and transporters. Therefore, ABL001 has high selectivity.
In vivo studies
In KCL-22 mouse transplanted tumor model, ABL001 has effective anti-tumor activity, can cause complete tumor regression, and has a concentration-dependent relationship with pSTAT5 inhibitory effect. ABL001 has moderate oral absorption, in vivo volume distribution and half-life. When administered as a single agent, it can induce clinical anti-tumor activity and is well tolerated in patients with CML (chronic myeloid leukemia) treated with multiple previous chemotherapy. As for its pharmacokinetics and pharmacodynamics, plasma clearance (CL) of 1mg/kg, 2mg/kg and 1mg/kg of ABL001 were 12, 16 and 6 mL/min/kg in mice, rats and dogs, respectively. In mice and dogs, a single intravenous injection of 1 mg/kg ABL001,T 1/2term was 1.1 and 3.7 hours, respectively. In rats, a single intravenous injection of 2 mg/kg,T 1/2term is 2.7 hours. After oral administration of 30 mg/kg ABL001 to mice and rats, the oral bioavailability was 35% and 27% respectively. In dogs, the oral bioavailability was 111% at 15 mg/kg ABL001.
biological activity | aspinib (ABL001) is a potent and selective allosteric inhibitor of abl1, the Kd values ranged from 0.5 to 0.8 μm and bound to the tetradecyl pocket of abl1. |
Target | TargetValue Abl1 (Cell-free assay) 0.45 nM |
Target | Value |
Abl1 (Cell-free assay) | 0.45 nM |
in vitro study | ABL001 is a potent and selective BCR-ABL inhibitor with activity on most mutant forms, such as T315I. Binding of ABL001 to the regulatory site of ABL1, which in wild-type ABL is usually occupied by a myristoyl group. ABL001 inhibits ABL kinase activity by an inhibitor mechanism that is different from other targeted catalytic sites. It binds to the pocket of the BCR-ABL kinase region, which, under normal conditions, is occupied by the N-terminal ten-alkyl of ABL1, and once bound to BCR, N-terminal loss of eighteen alkylations acting on the ABL 1 self-regulating function. By binding to this blank site, ABL001 mimics the effect of the N-terminal of the eighteen alkyl group, thereby restoring the negative regulatory function of the kinase activity. ABL001 at concentrations of 1-10 nM selectively inhibited the growth of CML and Ph ALL cells; Whereas BCR-ABL-negative cells were unaffected by ABL001 even at concentrations as high as 1000-fold or more. The dissociation constant Kd for the binding of ABL001 to The myristoyl pocket of ABL is 0.5-0.8 nM, inducing an inactivated C- terminal helical conformation. ABL001 was not active on more than 60 kinases tested, including SRC, nor on G protein-coupled receptors, ion channels, nuclear receptors, and transporters. Thus ABL001 has high selectivity. |
in vivo studies | ABL001 has potent anti-tumor activity in a KCL-22 mouse xenograft model, can cause complete tumor regression, and the inhibitory effect of pSTAT5 in a concentration-dependent relationship. ABL001 has moderate oral absorption, in vivo volume distribution, and half-life. When administered as a single agent, it can induce clinical anti-tumor activity and is well tolerated in CML (chronic myeloid leukemia) patients who have received multiple chemotherapies. For its pharmacokinetics, pharmacodynamics, in mice, rats and dogs in a single intravenous injection of 1 mg/kg, 2 mg/kg and 1 mg/kg of ABL001, plasma clearance (CL) 12, 16 and 6 mL/min/kg, respectively. In mice and dogs, T 1/2term was 1.1 and 3.7 hours, respectively, with a single intravenous injection of 1 mg/kg ABL001. In rats, a single intravenous injection of 2 mg/kg,T 1/2term for 2.7 hours. After oral administration of 30 mg/kg ABL001 to mice and rats, the oral bioavailability was 35% and 27%, respectively; While in dogs, oral administration of 15 mg/kg ABL001, the oral bioavailability was 111%. |