5TO8

Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency

Summary for 5TO8

• Entry DOI: 10.2210/pdb5to8/pdb
• Descriptor: Protein-tyrosine kinase 2-beta, 25-(methylsulfonyl)-8-(trifluoromethyl)-5,17,18,21,22,23,24,25-octahydro-12H-7,11-(azeno)-16,13-(metheno)pyrido[3,2-i]pyrrolo[1,2-q][1,3,7,11,17]pentaazacyclohenicosin-20(6H)-one (3 entities in total)
• Functional Keywords: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q14289
• Total number of polymer chains: 1
• Total formula weight: 33141.33

Authors

Newby, Z.E. (deposition date: 2016-10-17, release date: 2016-12-21, Last modification date: 2024-03-06)

Primary citation

Farand, J.,Mai, N.,Chandrasekhar, J.,Newby, Z.E.,Van Veldhuizen, J.,Loyer-Drew, J.,Venkataramani, C.,Guerrero, J.,Kwok, A.,Li, N.,Zherebina, Y.,Wilbert, S.,Zablocki, J.,Phillips, G.,Watkins, W.J.,Mourey, R.,Notte, G.T.
Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency.
Bioorg. Med. Chem. Lett., 26:5926-5930, 2016

PubMed Abstract: Herein, we describe the synthesis of Pyk2 inhibitors via macrocyclization of FAK and dual Pyk2-FAK inhibitors. We identified macrocycle 25a as a highly potent Pyk2 inhibitor (IC=0.7nM), with ∼175-fold improvement in Pyk2 potency as compared to its acyclic counterpart. In many cases, macrocyclization improved Pyk2 potency while weakening FAK potency, thereby improving the Pyk2/FAK selectivity ratio for this structural class of inhibitors. Various macrocyclic linkers were studied in an attempt to optimize Pyk2 selectivity. We observed macrocyclic atropisomerism during the synthesis of 19-membered macrocycles 10a-d, and successfully obtained crystallographic evidence of one atropisomer (10a-AtropB) preferentially bound to Pyk2.

PubMed: 27876318
DOI: 10.1016/j.bmcl.2016.10.092

Experimental method

X-RAY DIFFRACTION (1.9849 Å)