5FXQ

IGFR-1R complex with a pyrimidine inhibitor.

Summary for 5FXQ

• Entry DOI: 10.2210/pdb5fxq/pdb
• Related: 5FXR 5FXS
• Descriptor: INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR, 5-chloranyl-4-imidazo[1,2-a]pyridin-3-yl-N-(5-methyl-1-piperidin-4-yl-pyrazol-4-yl)pyrimidin-2-amine (3 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 35617.22

Authors

Degorce, S.,Boyd, S.,Curwen, J.,Ducray, R.,Halsall, C.,Jones, C.,Lach, F.,Lenz, E.,Pass, M.,Pass, S.,Trigwell, C.,Norman, R.,Phillips, C. (deposition date: 2016-03-02, release date: 2016-10-19, Last modification date: 2024-05-08)

Primary citation

Degorce, S.L.,Boyd, S.,Curwen, J.O.,Ducray, R.,Halsall, C.T.,Jones, C.D.,Lach, F.,Lenz, E.M.,Pass, M.,Pass, S.,Trigwell, C.
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).
J. Med. Chem., 59:4859-4866, 2016

PubMed 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.

PubMed: 27078757
DOI: 10.1021/acs.jmedchem.6b00203

Experimental method

X-RAY DIFFRACTION (2.3 Å)