compound 27 [PMID: 29775310]   Click here for help

GtoPdb Ligand ID: 9973

PDB Ligand
Compound class: Synthetic organic
Comment: Compound 27 is a lead ERK1/2 inhibitor that was identified using biophysical fragment screening and structure-based optimization [1]. It was found to be potent, selective and orally bioavailable. Compound 27 inhibits both the catalytic kinase (phosphorylating) activity of ERK1/2, and the phosphorylation of ERK1/2. It is an alternative chemotype to SCH772984, but it retains the dual activity profile that was originally identified in SCH772984. Compound 27 has improved in vivo exposure compared to SCH772984.
(Note: ERK1= MAPK3, ERK2= MAPK1).
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 9
Hydrogen bond donors 3
Rotatable bonds 9
Topological polar surface area 116.68
Molecular weight 549.21
XLogP 3.58
No. Lipinski's rules broken 0
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Canonical SMILES OCC(c1cccc(c1)C)NC(=O)C(N1Cc2c(C1=O)cc(cc2)c1nc(ncc1Cl)NC1CCOCC1)C
Isomeric SMILES OC[C@H](c1cccc(c1)C)NC(=O)[C@H](N1Cc2c(C1=O)cc(cc2)c1nc(ncc1Cl)NC1CCOCC1)C
InChI InChI=1S/C29H32ClN5O4/c1-17-4-3-5-19(12-17)25(16-36)33-27(37)18(2)35-15-21-7-6-20(13-23(21)28(35)38)26-24(30)14-31-29(34-26)32-22-8-10-39-11-9-22/h3-7,12-14,18,22,25,36H,8-11,15-16H2,1-2H3,(H,33,37)(H,31,32,34)/t18-,25-/m1/s1
Bioactivity Comments
Compound 27 reduced both pRSK (a downstream phosphorylation target of ERK, the IC50 for this effect is 3.5 nM) and pERK1/2 levels (IC50 2.3 nM) in mutant BRAF cells in vitro and in vivo [1], the latter action indicating potential utility in tumours with acquired resistance to current BRAF inhibitors. It also suppressed pERK and pRSK levels in human colon carcinoma (Colo205) xenograft models and xenograft regression was observed after 15 days of treatment.
Off-targets (kinases inhibited by >50% at 100 nM): protein kinases D1 and D2 (PRKD1, PRKD2), and mitogen-activated protein kinase 15 (MAPK15/ERK7). Further off-targets that are inhibited by >50% at 1 μM compound 27 are listed in Supplementary Table 1 [1].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
mitogen-activated protein kinase 1 Hs Inhibitor Inhibition 8.5 pIC50 - 1
pIC50 8.5 (IC50 3x10-9 M) [1]