PDBsum entry 4bzo

Transferase

PDB id: 4bzo

Contents

Protein chain

273 a.a.

Ligands

676

Waters ×135

References listed in PDB file

Key reference

• Title: Discovery and optimization of pyrrolo[1,2-A]pyrazinones leads to novel and selective inhibitors of pim kinases.
• Authors: F.Casuscelli, E.Ardini, N.Avanzi, E.Casale, G.Cervi, M.D'Anello, D.Donati, D.Faiardi, R.D.Ferguson, G.Fogliatto, A.Galvani, A.Marsiglio, D.G.Mirizzi, M.Montemartini, C.Orrenius, G.Papeo, C.Piutti, B.Salom, E.R.Felder.
• Ref.: Bioorg Med Chem Lett, 2013, 21, 7364-7380. [DOI no: 10.1016/j.bmc.2013.09.054]
• PubMed id: 24139169

Abstract

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.