compound 9 [PMID: 26006010]   

GtoPdb Ligand ID: 9761

Compound class: Synthetic organic
Comment: Compound 9 [PMID: 26006010] is a reversible BTK inhibitor that was designed to have a long target residency time with a resulting increase in the duration of in vivo target engagement, and with the overall aim of improving in vivo drug efficacy [1]. Compound 9 has a cysteine-reactive, inverted cyanoacrylamide scaffold structure that interacts with Cys481, a residue that lies outwith the catalytic domain of the enzyme but close to the ATP pocket (and is also a target of the irreversible inhibitor ibrutinib). It has good aqueous solubility and is orally bioavailable. Compound 9 may be PRN473 as described in [3], but PRN473's structure has not been formally disclosed.
2D Structure
Click here for structure editor
Physico-chemical Properties
Hydrogen bond acceptors 9
Hydrogen bond donors 1
Rotatable bonds 10
Topological polar surface area 135.42
Molecular weight 610.28
XLogP 4.03
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES N#CC(=CC(N(C1COC1)C)(C)C)C(=O)N1CCCC1Cn1nc(c2c1ncnc2N)c1ccc(cc1F)Oc1ccccc1
Isomeric SMILES N#C/C(=C\C(N(C1COC1)C)(C)C)/C(=O)N1CCC[C@H]1Cn1nc(c2c1ncnc2N)c1ccc(cc1F)Oc1ccccc1
InChI InChI=1S/C33H35FN8O3/c1-33(2,40(3)23-18-44-19-23)15-21(16-35)32(43)41-13-7-8-22(41)17-42-31-28(30(36)37-20-38-31)29(39-42)26-12-11-25(14-27(26)34)45-24-9-5-4-6-10-24/h4-6,9-12,14-15,20,22-23H,7-8,13,17-19H2,1-3H3,(H2,36,37,38)/b21-15+/t22-/m0/s1
InChI Key YELZMARZEBVKBL-VAZXNAHHSA-N
Bioactivity Comments
Compound 9 shows a good selectivity profile (only BTK and BMX were inhibited by >90% at 0.1 μM), and only other kinases with a conserved Cys481 were inhibited at 1 μM compound 9 [1]. In cells, compound 9 is selective for the B cell receptor pathway.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
Bruton tyrosine kinase Hs Inhibitor Inhibition 8.7 pIC50 - 1
pIC50 8.7 (IC50 1.9x10-9 M) [1]
tec protein tyrosine kinase Hs Inhibitor Inhibition 8.5 pIC50 - 1
pIC50 8.5 (IC50 3.4x10-9 M) [1]
BMX non-receptor tyrosine kinase Hs Inhibitor Inhibition 8.1 pIC50 - 1
pIC50 8.1 (IC50 7.6x10-9 M) [1]
TXK tyrosine kinase Hs Inhibitor Inhibition 7.4 pIC50 - 1
pIC50 7.4 (IC50 4.1x10-8 M) [1]
BLK proto-oncogene, Src family tyrosine kinase Hs Inhibitor Inhibition 7.2 pIC50 - 1
pIC50 7.2 (IC50 6.8x10-8 M) [1]
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
erb-b2 receptor tyrosine kinase 4 Hs Inhibitor Inhibition 7.2 pIC50 - 1
pIC50 7.2 (IC50 6.5x10-8 M) [1]