PDBsum entry 5fxq

Transferase

PDB id: 5fxq

Contents

Protein chain

302 a.a.

Ligands

GD5

Waters ×242

References listed in PDB file

Key reference

• Title: Discovery of a potent, Selective, Orally bioavailable, And efficacious novel 2-(Pyrazol-4-Ylamino)-Pyrimidine inhibitor of the insulin-Like growth factor-1 receptor (igf-1r).
• Authors: S.L.Degorce, S.Boyd, J.O.Curwen, R.Ducray, C.T.Halsall, C.D.Jones, F.Lach, E.M.Lenz, M.Pass, S.Pass, C.Trigwell.
• Ref.: J Med Chem, 2016, 59, 4859-4866. [DOI no: 10.1021/acs.jmedchem.6b00203]
• PubMed id: 27078757

Abstract

Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.