| In Vitro | AT-406 is a Smac mimetic and appears to mimic closely the AVPI peptide in both hydrogen bonding and hydrophobic interactions with XIAP, with additional hydrophobic contacts with W323 of XIAP. AT-406 is more sensitive to these IAPs than Smac AVPI peptide with 50-100 fold binding affinities. AT-406 (at 1 μM) completely restores the activity of caspase-9, which is suppressed by 500 nM XIAP BIR3 in a cell-free system. |
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| In Vivo | AT-406 has good pharmacokinetic (PK) properties and oral bioavailability in mice, rats, non-human primates, and dogs. In the MDA-MB-231 xenograft, AT-406 effectively induces cIAP1 degradation and processing of procaspase-8, cleavage of PARP in tumor tissues at 100 mg/kg with well toleration even at 200 mg/kg. AT-406 induces significant tumor growth inhibition with p of 0.0012 at 100 mg/kg. |
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| Animal model | MDA-MB-231 xenograft tumors in severe combined immune deficiency (SCID) mice |
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| Formulation & Dosage | HCl salt form of AT-406 in water; 10, 30, 100 mg/kg; Oral |
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| References | [1] Cai Q, et al. J Med Chem, 2011, 54(8), 2714-2726. |
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