PDBsum entry 3dtc

Transferase

PDB id: 3dtc

Contents

Protein chain

245 a.a.

Ligands

SO4

VIN

Waters ×43

References listed in PDB file

Key reference

• Title: Mixed-Lineage kinase 1 and mixed-Lineage kinase 3 subtype-Selective dihydronaphthyl[3,4-A]pyrrolo[3,4-C]carbazole-5-Ones: optimization, Mixed-Lineage kinase 1 crystallography, And oral in vivo activity in 1-Methyl-4-Phenyltetrahydropyridine models.
• Authors: R.L.Hudkins, J.L.Diebold, M.Tao, K.A.Josef, C.H.Park, T.S.Angeles, L.D.Aimone, J.Husten, M.A.Ator, S.L.Meyer, B.P.Holskin, J.T.Durkin, A.A.Fedorov, E.V.Fedorov, S.C.Almo, J.R.Mathiasen, D.Bozyczko-Coyne, M.S.Saporito, R.W.Scott, J.P.Mallamo.
• Ref.: J Med Chem, 2008, 51, 5680-5689.
• PubMed id: 18714982

Abstract

The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.