KRCA-0008 is a potent and selective ALK/Ack1 inhibitor with IC50 of 12 nM/4 nM forALK and Ack1 respectively and displays drug-like properties without hERG liability.
Anaplastic lymphoma kinase (ALK) belongs to the insulin receptor superfamily of tyrosine kinase. ALK-fused genes such as NPMALK, EML4-ALK, KIF5-ALK are putative oncogenes and responsible for many cancers including anaplastic large-cell lymphomas (ALCL), inflammatory myofibroblastic tumors (IMT), diffuse large B cell lymphoma (DLBCL) and a variety of solid tumor types [2]. KRCA-0008 is selective and potent to ALK and Ack1 with IC50 of 12 nM, 4 nM respectively, and has drug-like properties without hERG concerns [3].KRCA-0008 has good water-solubility with moderate plasma protein binding (93% in rat) and low brain exposure (Cbrain /C plasma =~0.02). It has good liver microsomal stability (% remaining after 30 min: 52% in mouse, 89% in rat, 72% inhuman). It does not appear to cause hERG blockade (patch clamp IC50=30 μM) and is negative on Ames test (1000 μg/plate), chro-mosomal aberration assay and micronucleus assay. KRCA-0008 also shows promising pharmacokinetic parameters in both mice and rat (oral bioavailability = 66–94.5%). Finally, KRCA-0008 shows a modest tumor growth inhibition in vivo activity in H3122 human lung cancer bearing mice model comparable to Crizotinib without significant body weight change. The KRCA-0008 25 mpk and 50 mpk groups did not show dose-dependent tumor growth inhibition. [2].
作用机制
Ligand interactions of KRCA-0008 display two hydrogen bonds with the backbone amide hydrogen and carbonyl oxygen of M1199 in the hinge region. The chlorine on the B-ring C5 position has hydrophobic interaction to L1196 as well as B-ring has CH/Π interaction with A1148 [4].
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