PDBsum entry 5fi4

Transferase/transferase inhibitor

PDB id: 5fi4

Contents

Protein chains

1009 a.a.

249 a.a.

Ligands

GOL

5XV

Waters ×263

PDB id:

5fi4

Name:

Transferase/transferase inhibitor

Title:

Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-pi3 kinases that are efficacious in a mouse xenograft model

Structure:

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform. Chain: a. Synonym: ptdins-3-kinase subunit alpha,phosphatidylinositol 4,5- bisphosphate 3-kinase 110 kda catalytic subunit alpha,p110alpha, phosphoinositide-3-kinase catalytic alpha polypeptide, serine/threonine protein kinase pik3ca. Engineered: yes. Mutation: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3ca. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: pik3r1.

Resolution:

2.50Å R-factor: 0.196 R-free: 0.245

Authors:

R.A.Elling,M.S.Knapp,W.Han,L.M.Daniel,Y.Xy,M.T.Burger,Z.Ni,A.Smith, J.Lan,T.Williams,J.Verhagen,K.Huh,H.Merritt,J.Chan,S.Kaufman, C.F.Voliva,S.Pecchi

Key ref:

W.Han et al. (2016). Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model. Bioorg Med Chem Lett, 26, 742-746. PubMed id: 26774655 DOI: 10.1016/j.bmcl.2016.01.003

Date:

22-Dec-15 Release date: 03-Feb-16

Protein chain

P42336  (PK3CA_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform from Homo sapiens

Seq: 1068 a.a.

Struc: 1009 a.a.

Protein chain

P27986  (P85A_HUMAN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha from Homo sapiens

Seq: 724 a.a.

Struc: 249 a.a.

Enzyme reactions

• Enzyme class 2: Chain A: E.C.2.7.1.137 - phosphatidylinositol 3-kinase.
• Pathway: 1-Phosphatidyl-myo-inositol Metabolism
• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H⁺
• Enzyme class 3: Chain A: E.C.2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate) + ADP + H⁺
• Enzyme class 4: Chain A: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 5: Chain B: E.C.?

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.bmcl.2016.01.003

Bioorg Med Chem Lett 26:742-746 (2016)

PubMed id: 26774655

Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.

W.Han, D.L.Menezes, Y.Xu, M.S.Knapp, R.Elling, M.T.Burger, Z.J.Ni, A.Smith, J.Lan, T.E.Williams, J.Verhagen, K.Huh, H.Merritt, J.Chan, S.Kaufman, C.F.Voliva, S.Pecchi.

ABSTRACT

Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.