4KZ0

Structure of PI3K gamma with Imidazopyridine inhibitors

Summary for 4KZ0

• Entry DOI: 10.2210/pdb4kz0/pdb
• Related: 4KZC
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, methyl 2-(acetylamino)-1,3-benzothiazole-6-carboxylate, SULFATE ION, ... (4 entities in total)
• Functional Keywords: lipid kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111102.50

Authors

Knapp, M.S.,Elling, R.A. (deposition date: 2013-05-29, release date: 2013-07-17, Last modification date: 2024-02-28)

Primary citation

Pecchi, S.,Ni, Z.J.,Han, W.,Smith, A.,Lan, J.,Burger, M.,Merritt, H.,Wiesmann, M.,Chan, J.,Kaufman, S.,Knapp, M.S.,Janssen, J.,Huh, K.,Voliva, C.F.
Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K.
Bioorg.Med.Chem.Lett., 23:4652-4656, 2013

PubMed Abstract: PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.

PubMed: 23820386
DOI: 10.1016/j.bmcl.2013.06.010

Experimental method

X-RAY DIFFRACTION (2.87 Å)