A-443654   Click here for help

GtoPdb Ligand ID: 8204

Synonyms: A 443654 | A443654
PDB Ligand
Compound class: Synthetic organic
Comment: A-443654 is an ATP-competitive inhibitor of all three Akt (protein kinase B) subtypes [2], but causes paradixical hyperphosphorylation of two regulatory amino acid residues (Thr308 and Ser473) of the Akt protein [1,3]. A-443654 exhibits modest selectivity for Akt, compared to other AGC family kinases, such as PKA and PKC [2].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 3
Hydrogen bond donors 3
Rotatable bonds 6
Topological polar surface area 92.61
Molecular weight 397.19
XLogP 4.17
No. Lipinski's rules broken 0
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Canonical SMILES NC(Cc1c[nH]c2c1cccc2)COc1cncc(c1)c1ccc2c(c1)c(C)n[nH]2
Isomeric SMILES N[C@@H](Cc1c[nH]c2c1cccc2)COc1cncc(c1)c1ccc2c(c1)c(C)n[nH]2
InChI InChI=1S/C24H23N5O/c1-15-22-10-16(6-7-24(22)29-28-15)17-9-20(13-26-11-17)30-14-19(25)8-18-12-27-23-5-3-2-4-21(18)23/h2-7,9-13,19,27H,8,14,25H2,1H3,(H,28,29)/t19-/m0/s1
Bioactivity Comments
In a selectivity profile screen of 220 kinases, A-443654 is reported to inhibit 47 additional kinases by >90% using 1μM compound [3]. These off-targets include CAMK2D, MRCK alpha and beta, CLK1, -2 and -3, DYRK1A, -1B and -3, GRK7, GSK3β, the MAP kinases GCK, HGK and KHS1, MINK1 and others [3].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
AKT serine/threonine kinase 1 Primary target of this compound Hs Inhibitor Inhibition 9.8 pKi - 2
pKi 9.8 (Ki 1.6x10-10 M) [2]
AKT serine/threonine kinase 2 Hs Inhibitor Inhibition ~9.8 pKi - 2
pKi ~9.8 (Ki ~1.6x10-10 M) [2]
AKT serine/threonine kinase 3 Hs Inhibitor Inhibition ~9.8 pKi - 2
pKi ~9.8 (Ki ~1.6x10-10 M) [2]
CDC42 binding protein kinase beta Hs Inhibitor Inhibition - - - 3
Description: Measured as % inhibition using 1μM compound.
phosphorylase kinase catalytic subunit gamma 1 Hs Inhibitor Inhibition - - - 3
Description: Measured as % inhibition using 1μM compound.